Proline derivatives and the use thereof as drugs

ABSTRACT

The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products.  
     The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I)  
                 
 
     wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.

TECHNICAL FIELD

[0001] The present invention relates to a proline derivative showing adipeptidyl peptidase IV (DPP-IV) inhibitory activity, which is usefulfor the treatment or prophylaxis of diabetes, obesity, HIV infection,cancer metastasis, dermopathy, prostatic hyperplasia, periodontitis,autoimmune disease and the like, and a salt thereof.

BACKGROUND ART

[0002] DPP-IV is a serine protease, which recognizes an amino acidsequence having proline (or alanine or hydroxyproline) the penultimateposition from the N-terminal and produces dipeptide Xaa-Pro (Xaa showsan optional amino acid and Pro shows L-proline). DPP-IV is widelydistributed in mammalian tissues and is known to be present particularlyin blood, kidney, intestinal epithelium and placenta.

[0003] While the physiological role of DPP-IV in mammal has not beencompletely elucidated, its involvement in a broad range of functions ofliving organisms such as degradation of neuropeptide [Heymann et al.,FEBS Letters vol. 91, 360-364 (1978)], activation of T cell [Schon etal., Biomedica Biochimica Acta vol. 44, K9-K15 (1985)], adhesion ofmetastatic tumor cell to endothelium [Johnson et al., Journal of CellBiology, vol. 121, 1423-1432 (1993)], invasion of HIV virus intolymphocytes [Callebaut et al., Science vol. 262, 2045-2050 (1993)] andthe like is being clarified. Of these, the role of DPP-IV as an enzymethat inactivates glucagon-like peptide (GLP-1), which is a biogenicsubstance having a strong insulin secretion ability and controlspostprandial blood glucose level, has been drawing attention [Deacon etal., Journal of Clinical Endocrinology and Metabolism, vol. 80, 952-957(1995)].

[0004] GLP-1 is known to be metabolized in several minutes in a livingorganism. In the metabolism, that by DPP-IV is particularly important,because it quickly cleaves GLP-1 and produces inert GLP-1 [Deacon etal., American Journal of Physiology, vol. 271, E458-E464 (1996)]. Inaddition, it is considered that physiological action of GLP-1 becomesattenuated further because this inert GLP-1 shows an antagonistic actionon GLP-1 receptor [Knudsen et al., European Journal of Pharmacology,vol. 318, 429-435 (1996)]. Therefore, a method for suppressing cleavageof GLP-1 by inhibition of DPP-IV is considered to be the most superiorapproach for reinforcing GLP-1 action. That is, a DPP-IV inhibitor isexpected to be a superior treatment method of curing postprandialhyperglycemia without side effects, such as prolonged hypoglycemia andthe like, for non insulin-dependent diabetic (type II diabetes)patients.

[0005] Patent applications relating to DPP-IV inhibitors include thefollowing.

[0006] Japanese Patent Application under PCT laid-open under kohyo No.9-509921 discloses (S)-2-cyano-1-L-prolinepyrrolidine derivative. TheL-α-amino acid corresponding to the L-proline moiety of the compounddisclosed therein characteristically has a lipophilic side chain.

[0007] In addition, WO99/61431 describes DPP-IV inhibitory activities ofa compound consisting of natural amino acid and thiazolidine orpyrrolidine.

DISCLOSURE OF THE INVENTION

[0008] While there have been reported many DPP-IV inhibitors till date[Augustyns et al., Current Medicinal Chemistry, vol. 6, 311-327 (1999)],none of the compounds shows sufficient inhibitory activity or sufficientstability and safety in living organisms, and they are unsatisfactory asa pharmaceutical product. Therefore, the development of a compound whichexhibits a therapeutic effect through the inhibition of DPP-IV actionand satisfactory as a pharmaceutical product has been demanded.

[0009] In view of the above-mentioned points, the present inventors haveconducted intensive studies with the aim of developing a novel DPP-IVinhibitor. As a result, the present inventors have found that aderivative having a substituent introduced into the γ-position ofproline has a potent DPP-IV inhibitory activity, and made the stabilityhigher, which resulted in the completion of the present invention.

[0010] Accordingly, the present invention relates to the followingcompounds.

[0011] (1) An L-proline derivative of the formula (I)

[0012] wherein

[0013] X shows —NR¹R² wherein R¹ and R² may be the same or different andeach is independently a hydrogen atom, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or maybe bonded to each other to form a heterocycle optionally containing 1 or2 nitrogen atoms or oxygen atoms, the heterocycle optionally beingcondensed with an aromatic ring optionally having substituents, and theheterocycle optionally being a spiro ring,

[0014] —NR³COR⁴ wherein R³ and R⁴ are the same or different and each isindependently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,

[0015] —NR⁵CONR⁶R⁷ or —NR⁵CH₂CH₂NR⁶R⁷ wherein R⁵, R⁶ and R⁷ are the sameor different and each is independently hydrogen atom, alkyl, acyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or R⁶ and R⁷ may be bonded to each other to form aheterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms,the heterocycle optionally being condensed with an aromatic ringoptionally having substituents,

[0016] —NR⁸SO₂R⁹ wherein R⁸ and R⁹ are the same or different and each isindependently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl, or

[0017] —OR¹⁰ or —OCOR¹¹ wherein R¹⁰ and R¹¹ are each a hydrogen atom,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl,

[0018] Y is CH₂, CH—OH, S, S═O or SO₂,

[0019] Z is a hydrogen atom or a cyano, and of the above-mentionedgroups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle eachoptionally have substituents,

[0020] or a pharmaceutically acceptable salt thereof.

[0021] (2) The L-proline derivative described in the aforementioned (1),wherein X of the formula (I) is a substituent selected from the formulas

[0022] wherein

[0023]

is a single bond or a double bond,

[0024] R¹² is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, —NR¹⁴R¹⁵, —OR¹⁶, —COR¹⁷, —CO₂R¹⁸,—CONR¹⁹R²⁰ or —SO₂R²¹CH₂ wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ andR²¹ are the same or different and each is independently a hydrogen atom,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl or haloalkyl, or R¹⁴ and R¹⁵, and R¹⁹ and R²⁰ may bebonded to each other to form heterocycles each optionally containing 1or 2 nitrogen atoms or oxygen atoms, said heterocycle optionally beingcondensed with an aromatic ring optionally having substituents,

[0025] R¹³ is a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl,

[0026] m is 1 or 2, and

[0027] A is a carbon atom or a nitrogen atom,

[0028] provided that i) when A is a carbon atom, A may be substituted bya hydroxyl group, carboxyl or alkoxycarbonyl, and ii) when A is anitrogen atom,

[0029]

is a single bond,

[0030] of the above-mentioned groups, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl andheterocycle each optionally have substituents,

[0031] or a pharmaceutically acceptable salt thereof.

[0032] (3) The L-proline derivative described in the aforementioned (1)or (2), wherein X of the formula (I) is a substituent selected from theformulas

[0033] wherein

[0034] R²² is a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl,

[0035] R²³ and R²⁴ are the same or different and each is independently ahydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,halogen, haloalkyl, cyano, nitro, —NR²⁵R²⁶, —NHSO₂R²⁷, —OR²⁸, —COOR²⁹,—CONHSO₂R³⁰, —SO₂OR³¹, —SO₂R³² or —CONR³³R³⁴ wherein R²⁵, R²⁶, R²⁷, R²⁸,R²⁹, R³⁰R³¹, R³², R³³ and R³⁴ are the same or different and each isindependently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, or R²⁵ and R²⁶, andR³³ and R³⁴ may be bonded to each other to form heterocycles eachoptionally containing 1 or 2 nitrogen atoms or oxygen atoms, saidheterocycle optionally being condensed with an aromatic ring optionallyhaving substituents,

[0036] a, b, c, d, e, f and g are all carbon atoms, or any one or twothereof is(are) nitrogen atom(s) and the rest is a carbon atom,

[0037] n is 0, 1, 2 or 3, and

[0038] A is a carbon atom or a nitrogen atom,

[0039] provided that when A is a carbon atom, A may be substituted by ahydroxyl group, carboxyl or alkoxycarbonyl, and

[0040] of the above-mentioned groups, alkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycleeach optionally have substituents,

[0041] or a pharmaceutically acceptable salt thereof.

[0042] (4) The L-proline derivative of any of the aforementioned (1) to(3), wherein, in the formula (I), the asymmetric carbon, to which X isbonded, is expressed by an S configuration, X is a group of the formula(VI) or (VII), R²³ and R²⁴ are the same or different and each is nitro,cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, halogen or haloalkyl, Y is a sulfur atomand Z is a hydrogen atom,

[0043] or a pharmaceutically acceptable salt thereof.

[0044] (5) The L-proline derivative of the aforementioned (1), wherein,in the formula (I), X is a hydroxyl group, phenylamino optionally havingsubstituents, 2-pyridylamino optionally having substituents,3-pyridazinylamino optionally having substituents or 2-pyrimidinylaminooptionally having substituents, and the asymmetric carbon, to which X isbonded, is expressed by an S configuration, or a pharmaceuticallyacceptable salt thereof.

[0045] (6) A compound of the formula (I-a)

[0046] wherein

[0047] X shows —NR¹R² wherein R¹ and R² may be the same or different andeach is independently a hydrogen atom, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or maybe bonded to each other to form a heterocycle optionally containing 1 or2 nitrogen atoms or oxygen atoms, the heterocycle optionally beingcondensed with an aromatic ring optionally having substituents, and theheterocycle optionally being a spiro ring,

[0048] —NR³COR⁴ wherein R³ and R⁴ are the same or different and each isindependently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,

[0049] —NR⁵CONR⁶R⁷ or —NR⁵CH₂CH₂NR⁶R⁷ wherein R⁵, R⁶ and R⁷ are the sameor different and each is independently a hydrogen atom, alkyl, acyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or R⁶ and R⁷ may be bonded to each other to form aheterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms,said heterocycle optionally being condensed with an aromatic ringoptionally having substituents, or

[0050] —NR⁸SO₂R⁹ wherein R⁸ and R⁹ are the same or different and each isindependently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl,

[0051] Y is CH₂, CH—OH, S, S═O or SO₂,

[0052] Z is a hydrogen atom or a cyano,

[0053] R³⁵ is —COR⁴¹ wherein R⁴¹ is a hydrogen atom, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or—COOR⁴² wherein R⁴² is alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl, and

[0054] of the above-mentioned groups, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl,heteroarylalkyl and heterocycle each optionally have substituents.

[0055] (7) A compound of the formula (I-b)

[0056] wherein

[0057] Z is a hydrogen atom or a cyano, and

[0058] R³⁵ is —COR⁴¹ wherein R⁴¹ is a hydrogen atom, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or—COOR⁴² wherein R⁴² is alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl, and

[0059] of the above-mentioned groups, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl eachoptionally have substituents.

[0060] The present invention further relates to the followingcompositions for pharmaceutical agents.

[0061] (8) A pharmaceutical composition containing an L-prolinederivative of any of the aforementioned (1)-(5) or a pharmaceuticallyacceptable salt thereof, and a pharmacologically acceptable carrier.

[0062] (9) A DPP-IV inhibitor containing an L-proline derivative of anyof the aforementioned (1)-(5) or a pharmaceutically acceptable saltthereof as an active ingredient.

[0063] (10) A therapeutic agent for the disease where DPP-IV isinvolved, which contains an L-proline derivative of any of theaforementioned (1)-(5) or a pharmaceutically acceptable salt thereof asan active ingredient.

[0064] (11) The therapeutic agent of the aforementioned (10), whereinthe aforementioned disease is diabetes, obesity, HIV infection, cancermetastasis, dermopathy, prostatic hyperplasia, periodontitis orautoimmune disease.

[0065] The symbols used in the present specification are explained inthe following.

[0066] Alkyl is preferably linear or branched alkyl having 1 to 8 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl, octyl and the like.

[0067] Acyl is preferably linear or branched and has 1 to 8 carbonatoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, hexanoyl and the like.

[0068] Cycloalkyl preferably has 3 to 7 carbon atoms, and is exemplifiedby cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0069] Cycloalkylalkyl has a cycloalkyl moiety, which is equivalent tothat mentioned above, and an alkyl moiety which is preferably linear orbranched and has 1 to 3 carbon atoms. Examples thereof includecyclopropylmethyl, 2-cyclobutylethyl, 3-cyclopentylpropyl,cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the like.

[0070] Aryl is preferably phenyl, naphthyl or ortho fused bicyclic grouphaving 8 to 10 ring atoms wherein at least one ring is an aromatic ring(e.g., indenyl) and the like.

[0071] Arylalkyl has an aryl moiety, which is equivalent to thatmentioned above, and an alkyl moiety which is preferably linear orbranched and has 1 to 3 carbon atoms. Examples thereof include benzyl,benzhydryl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl,2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-(2-naphthyl)propyl and thelike.

[0072] Arylalkenyl has an aryl moiety, which is equivalent to thatmentioned above, and an alkenyl moiety which has 2 or 3 carbon atoms andis linear or branched. Examples thereof include styryl and the like.

[0073] Heteroaryl is preferably a 5 or 6-membered ring group havingcarbon and 1-4 hetero atoms (oxygen, sulfur or nitrogen), an ortho fusedbicyclic heteroaryl having 8 to 10 ring atoms, which is derivedtherefrom, particularly a benz derivative, those derived from fusing apropenylene, trimethylene or tetramethylene group therewith, stableN-oxide thereof and the like. Examples thereof include pyrrolyl, furyl,thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzimidazolyl, oxazolopyridyl, imidazopyridazinyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, benzothienyl,chromenyl, isoindolyl, indolyl, indolinyl, indazolyl, isoquinolyl,quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl,2,1,3-benzoxadiazolyl, benzoxazinyl and the like.

[0074] Heteroarylalkyl has a heteroaryl moiety, which is equivalent tothat mentioned above, and an alkyl moiety which is preferably has 1 to 3carbon atoms and linear or branched. Examples thereof include2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-thienylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl,2-(4-pyridyl)ethyl, 3-(2-pyrrolyl)propyl, 4-imidazolylmethyl and thelike.

[0075] Heterocycle is a saturated or unsaturated monocyclic 4 to7-membered ring group or 10 or 11-membered ring group, which is a spiroring, having carbon and at least one nitrogen, and optionally otherhetero atom (oxygen or sulfur). Examples thereof include azetidinyl,pyrrolidinyl, piperidino, piperazinyl, morpholino, 1,4-diazepanyl,1,2,5,6-tetrahydropyridyl, thiomorpholino, oxothiomorpholino,dioxothiomorpholino, 3-azaspiro[5,5]undecyl, 1,3,8-triazaspiro[4,5]decyland the like.

[0076] Moreover, the above-mentioned heterocycle may be condensed withan aromatic ring (e.g., benzene ring, pyridine ring and the like)optionally having substituents. Examples thereof include indolinyl,isoindolinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl,phthalimido, indolyl and the like.

[0077] Halogen is exemplified by chlorine, bromine, fluorine and iodine.

[0078] Haloalkyl is exemplified by trifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like.

[0079] Of the above-mentioned substituents, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl,heteroarylalkyl and heterocycle are optionally substituted by thefollowing 1 or more substituents.

[0080] The substituents may be, for example, halogen, hydroxyl group,nitro, cyano, trifluoromethyl, alkyl, alkoxy, alkylthio, formyl,acyloxy, oxo, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-piperidinyl,2-morpholinoethyl, 3-picolyl, arylalkyl, —COOR_(a), —CH₂COOR_(a),—OCH₂COOR_(a), —CONR_(b)R_(c), —CH₂CQNR_(b) R_(c) (Q is ═O or ═S),—OCH₂CONR_(b)R_(c), —COO(CH₂)₂NR_(e)R_(f), —SO₂T₁, —CONR_(d)SO₂T₁,—NR_(e)R_(f), —NR_(g)CHO, —NR_(g)COT₂, —NR_(g)COOT₂,—NR_(g)CONR_(i)R_(j), —NR_(k)SO₂T₃, —SO₂NR_(l)R_(m), —SO₂NR_(n)COT₄,methylenedioxy, ethyleneoxy and the like.

[0081] These substituents may have substituents, and phenyl, 2-pyridyland 4-piperidinyl having substituents are exemplified by 4-cyanophenyl,4-chlorophenyl, 4-methoxyphenyl, 5-cyano-2-pyridyl,1-ethoxycarbonyl-4-piperidinyl and the like.

[0082] In the above-mentioned substituents of the substituents, halogen,alkyl and arylalkyl are exemplified by those mentioned above.

[0083] Alkoxy is linear or branched and preferably has 1 to 8 carbonatoms. Examples thereof include methoxy, ethoxy, propoxy, butoxy,pentyloxy, hexyloxy, octyloxy and the like. Alkylthio is linear orbranched and preferably has 1 to 8 carbon atoms. Examples thereofinclude methylthio, ethylthio, propylthio, butylthio, pentylthio,hexylthio, octylthio and the like. Acyloxy is linear or branched andpreferably has 1 to 8 carbon atoms. Examples thereof include formyloxy,acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy,hexanoyloxy, benzoyloxy and the like.

[0084] R_(a)-R_(n) show hydrogen, alkyl (as defined above) or arylalkyl(as defined above). R_(b) and R_(c), R_(e) and R_(f), R_(i) and R_(j),and R₁ and R_(m) of —NR_(b)R_(c), —NR_(e)R_(f), —NR_(i)R_(j) and—NR_(l)R_(m) may be respectively bonded to each other to formheterocycles each optionally having 1 or 2 nitrogen atoms or oxygenatoms, and the heterocycle may be condensed with an aromatic ringoptionally having substituents (as defined above, and optionallysubstituted by the aforementioned substituents). Moreover, —NR_(e)R_(f)may show a heteroaryl having ═O (e.g., 2-pyrrolidinon-1-yl, succinimido,oxazolidin-2-on-3-yl, 2-benzoxazolinon-3-yl, phthalimido,cis-hexahydrophthalimido and the like). T₁-T₄ show hydrogen atom, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl or haloalkyl, which may be substituted by theaforementioned substituents.

[0085] Due to the asymmetric carbon, to which X is bonded, in compound(I), compound (I) can be present as an optically active compound or adiastereomer mixture, and the diastereomer mixture can be separated intoeach optically active compound by a known method.

[0086] The compound (I) can show polymorphism, and can be present as twoor more tautomers.

[0087] Therefore, the present invention encompasses any of theabove-mentioned stereoisomers, optical isomers, polymorphs, tautomers,optional mixtures thereof and the like.

[0088] The pharmaceutically acceptable salt of compound (I) includes,for example, inorganic acid addition salts (e.g., salts withhydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,nitric acid, phosphoric acid and the like), organic acid addition salts(e.g., salts with methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid,oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid,adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid,malic acid, pantothenic acid, methylsulfuric acid and the like), saltswith. amino acids (e.g., salts with glutamic acid, aspartic acid and thelike), and the like.

[0089] The L-proline derivative of the present invention can be producedby the following method.

[0090] Scheme 1 shows a production method of a compound of the formula(I) wherein X is —OR¹⁰ or —OCOR¹¹.

[0091] wherein R³⁵ is an amino acid-protecting group (e.g.,tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz)), R³⁶ is ahydroxyl-protecting group (e.g., tert-butyldimethylmethylsilyl,triisopropylsilyl and tert-butyldiphenylsilyl), A′ is R¹⁰ or COR¹¹ andother symbols are as defined above.

[0092] When Z of a compound of the formula (VIII) is cyano, thiscompound can be prepared by a method described in a reference [Ashworthet al., Bioorganic & Medicainal Chemistry Letters, vol. 6, 1163-1166(1996)] or a conventional method based on such reference. A compound ofthe formula (IX′) [hereinafter to be referred to as compound (IX′)] canbe prepared by silylation of hydroxyl group of hydroxyproline derivativeby a conventional method.

[0093] Step a: Compound (VIII) is Reacted with Compound (IX) to GiveAmide Compound (XI), or Compound (VIII) is Reacted with Compound (IX′)to Give Amide Compound (X).

[0094] As a condensation agent for activating carboxylic acid ofcompound (IX) or (IX′), there are recited, for example,dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC), hydrochloridethereof, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (EEDQ),carbodiimidazole (CDI), diethylphosphoryl cyanide,benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate(PyBOP), diphenylphosphoryl azide (DPPA), isobutyl chloroformate,diethylacetyl chloride, trimethylacetyl chloride and the like. Thesecondensation agent may be used alone, or an additive such asN-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT) or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBT),4-dimethylaminopyridine (DMAP) and the like is used in combination.

[0095] This reaction is generally carried out in an inert solvent andthe inert solvent to be used may be any as long as it is aprotic.Preferable examples include acetonitrile, tetrahydrofuran,dichloromethane, chloroform, N,N-dimethylformamide (DMF) and the like.This condensation is carried out generally at a temperature of from −30°C. to 80° C., preferably from −10° C. to 25° C.

[0096] Step b: Compound (X) is Deprotected to Give Compound (XI′).

[0097] This reaction can be carried out in an inert solvent such astetrahydrofuran and the like, using tetrabutylammonium fluoride and thelike. The reaction mixture is preferably buffered with an acid such asacetic acid and the like generally at a temperature of from −30° C. to70° C. for 10 min to 24 hr.

[0098] Step c: Compound (XI) is Reacted to Give Compound (XII), orCompound (XI′) is Reacted to Give Compound (XII′).

[0099] By acylation of hydroxyl group of compound (XI) or (XI′) by ageneral method, a compound of the formula (XII) or (XII′), wherein A′ isCOR¹¹ ₁, can be obtained. The synthetic method of compound (XII) or(XII′), wherein R¹¹ is alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl, is exemplified by a methodincluding use of an active carboxylic acid derivative such as acidhalide, a method including use of a carboxylic acid and a couplingagent, and the like.

[0100] A compound of the formula (XII) or (XII′) wherein A′ is R¹⁰ canbe obtained by converting hydroxyl group of compound (XI) or (XI′) toalcoholate, which is followed by nucleophilic substitution of alkylhalide and the like. The reaction is carried out in the presence of abase such as sodium hydride and the like, using alkyl halide and thelike in an inert solvent such as tetrahydrofuran and the like, generallyat a temperature of from −80° C. to 60° C., preferably from −50° C. to25° C.

[0101] Step d: Compound (XI) is Reacted to Give Compound (XII′), orCompound (XI′) is Reacted to Give Compound (XII).

[0102] The reaction is carried out in the presence of phosphines such astriphenylphosphine, tributylphosphine and the like and diazodicarboxylicacid diester, using R¹¹COOH or aryl or heteroaryl having a hydroxylgroup, and the like in an inert solvent such as toluene, tetrahydrofuranand the like, generally at a temperature of from −30° C. to 110° C.,preferably from 0° C. to 25° C.

[0103] A compound of the formula (XII′) or (XII), wherein A′ is COR¹¹,can be obtained by sulfonylation of hydroxyl group of compound (XI) or(XI′), and reacting the compound with carboxylic acid salt. Thesulfonylation is carried out in the presence of a base such as pyridine,triethylamine and the like using p-toluenesulfonyl chloride,methanesulfonyl chloride, trifluoromethanesulfonyl chloride and thelike, in an inert solvent such as dichloromethane, 1,2-dichloroethaneand the like generally from −30° C. to 60° C. for 10 min to 24 hr. Thesubsequent reaction with carboxylic acid salt is carried out in thepresence of an inorganic base such as potassium carbonate, sodiumcarbonate and the like using R¹¹COOH in an inert solvent such asacetone, hexamethylphosphoramide and the like generally from 0° C. to120° C. for 10 min to 24 hr.

[0104] Step e: Compound (XII) is Deprotected to Give Compound (XIII), orCompound (XII′) is Deprotected to Give Compound (XIII′).

[0105] When, in this reaction, the protecting group is Boc group, forexample, the compound is reacted in a solvent such as acetonitrile,tetrahydrofuran, 1,4-dioxane, ethyl acetate, methanol, ethanol,chloroform and the like, using an acid such as hydrogen chloride,trifluoroacetic acid and the like generally from −30° C. to 60° C. for10 min to 24 hr for deprotection.

[0106] Scheme 2 shows a production method of a compound of the formula(I) wherein X is —NR¹R².

[0107] wherein OSO₂R³⁷ is a leaving group (e.g., tosylate (OTs),mesylate (OMs) or triflate (OTf)), Hal is halogen, R³⁸ and R³⁹ are thesame or different and each is independently hydrogen atom, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or may be bonded to each other to form a heterocycleoptionally containing 1 or 2 nitrogen atoms or oxygen atoms, or theheterocycle may be condensed with an aromatic ring optionally havingsubstituents, and other symbols are as defined above.

[0108] Step f: Hydroxyl Group of Compound (XI) is Sulfonylated to GiveCompound (XIV).

[0109] This reaction is carried out in the presence of a base such aspyridine, triethylamine and the like, using p-toluenesulfonyl chloride,methanesulfonyl chloride, trifluoromethanesulfonyl chloride and the likein an inert solvent such as dichloromethane, 1,2-dichloroethane and thelike generally at a temperature of from −30° C. to 60° C. for 10 min to24 hr.

[0110] Step g: Compound (XIV) is Subjected to Azidation to Give Compound(XV).

[0111] The reaction is carried out using a metal azide, such as s sodiumazide, in a solvent such as N,N-dimethylformamide and the like generallyat a temperature of from 0° C. to 120° C. for 30 min to 24 hr.

[0112] Step h: Compound (XV) is Directly Obtained from Compound (XI).

[0113] The reaction is carried out in the presence of phosphines such astriphenylphosphine, tributylphosphine and the like, anddiazodicarboxylic acid diester using hydrogen azide, DPPA, zinc azidebispyridine complex salt and the like in an inert solvent such astoluene, tetrahydrofuran and the like generally at a reactiontemperature of from −30° C. to 100° C.

[0114] Step i: Compound (XV) is Reduced to Give Compound (XVI).

[0115] For this reaction, catalytic reduction using palladium, platinum,nickel and the like, reduction by metalhydride, reduction bytriphenylphosphine, thiol, sulfide, diborane, or transition metal andthe like are mentioned.

[0116] Step j: Compound (XVI) is Reacted with Compound (XVII) or (XVII′)to Give Compound (XIX).

[0117] The reaction is carried out in the presence of a base such astriethylamine, diisopropylethylamine and the like in an inert solventsuch as N-methyl-2-pyrrolidone, N,N-dimethylformamide, tetrahydrofuranand the like at a temperature of from 0° C. to near boiling point ofsolvent, preferably from 0° C. to 80° C.

[0118] Step k: Compound (XVI) is Reacted with Compound (XVIII), which isFollowed by Reduction to Give Compound (XIX).

[0119] This reaction is carried out in the presence of sodiumborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride andthe like in an inert solvent such as methanol, ethanol, dichloromethane,1,2-dichloroethane, tetrahydrofuran, acetonitrile, 1,4-dioxane and thelike, and using, where necessary, an acid catalyst such as acetic acid,p-toluenesulfonic acid, boron trifluoride diethylether complex and thelike, generally at a temperature of from 0° C. to 100° C. for 10 min to20 hr.

[0120] By repeating Step j or k as necessary, compound (XIX) wherein R¹and R² may be the same or different can be obtained.

[0121] Step l: Compound (XIX) is Directly Obtained from Compound (XI).

[0122] The reaction is carried out in the presence of phosphines such astriphenylphosphine, tributylphosphine and the like and diazodicarboxylicacid diester using iminodicarbonates, sulfonamides, anitrogen-containing compound having N-H hydrogen and having highacidity, and the like in an inert solvent such as toluene,tetrahydrofuran and the like.

[0123] Step m: Compound (XI) is Oxidized to Give (XX).

[0124] This reaction is carried out by, for example, a method usingpyridine sulfur trioxide complex and dimethyl sulfoxide at roomtemperature. Examples of useful other methods include a method usingalkaline potassium permanganate solution; a method using oxalylchloride, dimethyl sulfoxide and tertiary amine; a method using aceticanhydride and dimethyl sulfoxide; a method using EDC and dimethylsulfoxide with dichloroacetic acid as a catalyst; a method usingchromium oxide (XI) pyridine complex in dichloromethane; a method usingaqueous sodium hypochlorite solution with TEMPO free radical as acatalyst in the presence of sodium bromide in ethyl acetate and toluene,and the like.

[0125] Step n: Compound (XX) is Reacted with Compound (XXI), which isFollowed by Reduction to Give Compound (XIX).

[0126] This reaction is carried out in the presence of sodiumborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride andthe like, in an inert solvent such as methanol, ethanol,dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile,1,4-dioxane and the like, and using as necessary an acidic catalyst,such as acetic acid, p-toluenesulfonic acid, boron trifluoride diethylether complex and the like generally at a temperature of from 0° C. to100° C. for 10 min to 20 hr.

[0127] The compound (XXI) can be synthesized by a known method. Step ois the same as Step e of Scheme 1.

[0128] The production method of a compound of the formula (I) wherein Xis —NR³COR⁴ is shown in Scheme 3.

[0129] wherein each symbol in the formula is as defined above.

[0130] The compound (XXIII) is the same as compound (XVI) obtained inScheme 2 or a compound (XIX) wherein one of R¹ and R² is hydrogen atom.

[0131] Step p: Compound (XXIII) is Reacted to Give Amide Compound(XXIV).

[0132] The reaction is carried out using R⁴COCl or R⁴CO₂H afterconversion to an acid halide with thionyl chloride, thionyl bromide andthe like or conversion to a mixed acid anhydride with pivaloyl chloride,isobutyl chloroformate and the like, in the presence of a tertiary basesuch as triethylamine, pyridine, N,N-dimethylaniline and the like, in aninert solvent such as toluene, hexane, tetrahydrofuran, 1,4-dioxane,ethyl acetate, chloroform, N,N-dimethylformamide, dimethyl sulfoxide,hexamethylphosphoramide and the like, generally from 0° C. to 120° C.for 10 min to 10 hr.

[0133] For the reaction with R⁴CO₂H, a condensation agent shown in Stepa can be also used and the reaction is carried out in an inert solventsuch as acetonitrile, tetrahydrofuran, dichloromethane, chloroform,N,N-dimethylformamide and the like generally at a temperature of from−30° C. to 80° C., preferably from −10° C. to 25° C.

[0134] Step q is the same as Step e of Scheme 1.

[0135] The production method of a compound of the formula (I) wherein Xis —NR⁵CONR⁶R⁷ is shown in Scheme 4.

[0136] wherein each symbol in the formula is as defined above.

[0137] The compound (XXVI) is the same as compound (XVI) obtained inScheme 2 or a compound (XIX) wherein one of R¹ and R² is hydrogen atom.

[0138] Step r: Compound (XXVI) is Reacted to Give Urea Compound (XXVII).

[0139] The reaction is carried out using isocyanate such as R⁶—NCO andthe like in an inert solvent such as toluene, chloroform,dichloromethane, tetrahydrofuran and the like generally at a temperatureof from −20° C. to 80° C., preferably from 0° C. to 25° C.

[0140] Alternatively, there is a method using, for example,carbodiimidazole, phosgene, diphosgene (trichloromethyl chloroformate),triphosgene [bis(trichloromethyl)carbonate] and the like, together withan amine represented by R⁶R⁷NH and a tertiary base such as triethylamineand the like.

[0141] Step s is the same as Step e of Scheme 1.

[0142] The production method of a compound of the formula (I) wherein Xis —NR⁸SO₂R⁹ is shown in Scheme 5.

[0143] wherein each symbol in the formula is as defined above.

[0144] The compound (XXIX) is the same as compound (XVI) obtained inScheme 2 or a compound (XIX) wherein one of R¹ and R² is hydrogen atom.

[0145] Step t: Compound (XXIX) is Reacted to Give Sulfonamide Compound(XXX).

[0146] The reaction is carried out using sulfonyl chloride such asR⁹—SO₂Cl and the like in the presence of an organic base such astriethylamine, pyridine and the like or an inorganic base such as sodiumcarbonate, potassium carbonate, sodium hydroxide and the like, in asolvent such as water, toluene, chloroform, dichloromethane,tetrahydrofuran and the like generally at a temperature of from −20° C.to 80° C.

[0147] Alternatively, there is a method wherein compound (XXIX) andsulfuryl chloride are reacted in the presence of a tertiary base such astriethylamine and the like in an inert solvent such as chloroform,dichloromethane, tetrahydrofuran and the like to give sulfamyl chloride,which is reacted with aryl compound in the presence of a Lewis acid suchas aluminum chloride and the like.

[0148] Step u is the same as Step e of Scheme 1.

[0149] A different production method of compound (XXII) is shown inScheme 6. This production method is useful when both R¹ and R² are nothydrogen atoms.

[0150] wherein R⁴⁰ is alkyl such as methyl, ethyl and the like, benzyland the like, and other symbols are as defined above.

[0151] Step v is the same as the method for conversion of compound (XI)to compound (XIX) shown in Scheme 2.

[0152] Step w: Ester-Protected Carboxyl Group of Compound (XXXIII) isDeprotected to Give Compound (XXXIV).

[0153] For reaction, general deprotection can be used. For example,sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate and the like are hydrolyzed under alkali conditions, or whenR⁴⁰ is benzyl, catalytic hydrogenation and the like are conducted in thepresence of platinum, palladium and the like, in an inert solvent suchas methanol, ethanol and the like for deprotection.

[0154] Step x: Compound (VIII) and Compound (XXXIV) are Reacted to GiveAmide Compound (XIX).

[0155] The reaction is carried out using a condensation agent shown inStep a, in an inert solvent such as acetonitrile, tetrahydrofuran,dichloromethane, chloroform, N,N-dimethylformamide and the likegenerally at a temperature of from −30° C. to 80° C., preferably from−10° C. to 25° C.

[0156] The compound of the formula (XXIV) shown in Scheme 3, thecompound of the formula (XXVII) shown in Scheme 4 and the compound ofthe formula (XXX) shown in Scheme 5 can be produced by the routes shownin Scheme 6.

[0157] The production method of compound (XXII), wherein the asymmetric,carbon, to which NR¹R² is bonded, is shown by S configuration, is shownin Scheme 2 using the compound of the formula (XI) as a startingmaterial, and in Scheme 6, using the compound of the formula (XXXII) asa starting material.

[0158] Besides the above-mentioned, a compound (XXII′), wherein theasymmetric carbon, to which NR¹R² is bonded, is shown by Rconfiguration,

[0159] wherein each symbol in the formula is as defined above, can bealso produced by a method similar to the one mentioned above usingcompound (XI′)

[0160] wherein each symbol in the formula is as defined above, or acompound (XXXII′)

[0161] wherein each symbol in the formula is as defined above, as astarting material.

[0162] When Z in each formula shows cyano, each compound up to anintermediate is produced with Z of the formula as a carbamoyl group anddehydrated by a known method for conversion thereof to cyano group.

[0163] This reaction is carried out using diphosphorus pentaoxide,phosphorus oxychloride-imidazole, trifluoroacetic acid anhydride,p-toluenesulfonyl chloride-pyridine and the like as a dehydrating agentin an inert solvent such as dichloromethane, pyridine and the like.

[0164] The L-proline derivative of the formula (I) of the presentinvention produced in this manner can be obtained at an optional purityby applying a known separation and purification means as necessary, suchas concentration, extraction, chromatography, reprecipitation,recrystallization and the like.

[0165] The L-proline derivative of the formula (I) can be prepared intoan acid addition salt as necessary with an inorganic acid such ashydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,nitric acid, phosphoric acid and the like or an organic acid such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citricacid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleicacid, tartaric acid, succinic acid, mandelic acid, malic acid,pantothenic acid, methylsulfuric acid and the like. In addition, it isalso present as a solvate such as hydrate and the like.

[0166] The compound of the formula (I) or a pharmacologically acceptablesalt of the present invention has a superior DPP-IV inhibitory activityin mammals (e.g., human, dog, cat, rat and the like).

[0167] Therefore, the compound of the present invention (I) or apharmacologically acceptable salt thereof is useful as a DPP-IVinhibitor and useful for the prophylaxis or treatment of variousdiseases considered to be caused by DPP-IV, for example, for theprophylaxis or treatment of diseases where GLP-1 is considered to beinvolved (e.g., diabetes, obesity and the like), and the like.

[0168] The compound (I) of the present invention can be administered toa same subject with other therapeutic drug for diabetes, therapeuticdrug for diabetic complications, anti-hyperlipidemic agent,antihypertensive agent and the like at the same time or timelag. As usedherein, examples of the therapeutic drug for diabetes include insulinsensitivity increasing agent, α-glucosidase inhibitor, biguanide agentand the like. Examples of the therapeutic drug for diabeticcomplications include aldose reductase inhibitor. As theanti-hyperlipidemic agent, statin compound, which is a cholesterolsynthetase inhibitor, squalene synthetase inhibitor, fibrates havingtriglyceride lowering effect, and the like can be mentioned. As theantihypertensive agent, calcium antagonist, angiotensin convertingenzyme inhibitor, angiotensin II antagonist and the like can bementioned. When the compound of the present invention is used oncombination with multiple agents, the mixing ratio thereof can beappropriately determined depending on the subject of administration, ageand body weight of the administration subject, symptom, administrationtime, dosage form, administration method, combination and the like.

[0169] When the compound (I) of the present invention or an acidaddition salt thereof is used as the aforementioned pharmaceuticalagent, it is used on its own or admixed with an appropriatepharmacologically acceptable carrier, an excipient, a diluent and thelike in the form of powder, granule, tablet, capsule, injection and thelike, and administered orally or parenterally. The above-mentionedpreparation contains an effective amount of compound (I) or apharmacologically acceptable salt thereof.

[0170] While the dose of the compound (I) or a pharmacologicallyacceptable salt thereof varies depending on the administration route,target disease, symptom, body weight and age of patients, and thecompound to be used, it can be determined as appropriately according tothe administration object. Generally, when orally administered to anadult, 0.01-1000 mg/kg body weight/day, preferably 0.05-500 mg/kg bodyweight/day, is preferably administered once a day or in several doses aday.

EXAMPLES

[0171] The present invention is explained in detail by referring toReference Examples and Examples, which are not to be construed aslimitative.

[0172]¹H-NMR was measured at 300 MHz unless particularly indicated. Thechemical shift of ¹H-NMR relative delta (δ) value was expressed in partsper million (ppm) using tetramethylsilane (TMS) as the internalstandard. For the coupling constant, obvious multiplicity is shown inhertz (Hz) using s (singlet), d (doublet), t (triplet), q (quartet),quint (quintet), m (multiplet), dd (doublet of doublets), td (triplet ofdoublets), brs (broad singlet) and the like. Thin-layer chromatographyused was manufactured by Merck, and column chromatography was performedusing silica gel manufactured by Fuji silysia chemical.

[0173] For drying organic solutions in extraction, anhydrous sodiumsulfate or anhydrous magnesium sulfate was used, unless particularlyindicated.

Reference Example 1

[0174] Synthesis of(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine

[0175] (1) N-tert-Butoxycarbonyl-L-cis-4-hydroxyproline (23.1 g) andimidazole (30.0 g) were dissolved in DMF (300 mL).tert-Butyldimethylsilyl chloride (33.3 g) was added thereto. Afterstirring at room temperature for 16 hr, water (300 mL) was graduallyadded under ice-cooling. The reaction solution was acidified with 10%aqueous citric acid solution and extracted with ethyl acetate. Theextract was washed 3 times with water and with brine, and dried. Thesolvent was distilled away under reduced pressure. The residue waspurified by silica gel chromatography to giveN-tert-butoxycarbonyl-L-cis-4-tert-butyldimethylsilyloxyproline (27.4 g)as a white solid.

[0176] (2) The above-mentioned compound (27.4 g) and(S)-2-cyanopyrrolidine hydrochloride (10.4 g) were dissolved in DMF (250mL), and triethylamine (10.9 mL), HOBT (14.3 g) and EDC hydrochloride(18.0 g) were added successively. The mixture was stirred at roomtemperature for 15 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution, and extracted with ethylacetate. The extract was washed with water and brine, and dried. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(25.3 g) as a slightly yellow oil.

[0177] (3) The above-mentioned compound (25.3 g) was dissolved intetrahydrofuran (300 mL), and a 1.0 mol/L solution (60 mL) oftetrabutylammonium fluoride in tetrahydrofuran was added dropwise underice-cooling. The mixture was stirred at room temperature for 3 hr, andthe solvent was evaporated under reduced pressure. The residue was addedto brine, and extracted with ethyl acetate. The extract was dried, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give the title compound (20.6g) as a white solid.

[0178]¹H-NMR(DMSO-d₆)δ1.25-1.45(9H,m), 1.50-1.64(1H,m), 1.95-2.30(4H,m),2.98-3.13(1H,m), 3.30-3.67(4H,m), 4.13-4.26(1H,m), 4.30-4.42(1H,m),4.77-4.88(1H,m), 5.16(1H,d,J=6.5 Hz).

Reference Example 2

[0179] Synthesis of(S)-1-((2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine

[0180] N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (68.4 g) and(S)-2-cyanopyrrolidine hydrochloride (39.2 g) were dissolved in DMF (350mL), and triethylamine (41.4 mL), HOBT (49.9 g), and EDC hydrochloride(62.5 g) were successively added. The mixture was stirred at roomtemperature for 15 hr. The reaction mixture was concentrated and brineand saturated aqueous sodium hydrogencarbonate solution were added tothe residue. The precipitated crystals were collected by filtration. Thefiltrate was extracted with ethyl acetate and the extract was dried. Thesolvent was evaporated under reduced pressure. The residue and thecrystals were combined and washed with ethyl acetate to give the titlecompound (60.7 g) as a white solid.

[0181]¹H-NMR(CDCl₃)δ1.30-1.45(9H,m), 1.54-2.38(5H,m), 3.30-3.93(5H,m),4.49-4.89(3H,m).

Reference Example 3

[0182] Synthesis of(S)-1-((2S,4S)-4-amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine

[0183] (1)(S)-1-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(title compound of Reference Example 2, 60.7 g) and triethylamine (30.1mL) were dissolved in DMF (300 mL). Methanesulfonyl chloride (16 mL) wasadded thereto under ice-cooling. After stirring at room temperature for3 hr, the reaction mixture was washed with water and dried. The solventwas evaporated under reduced pressure. Ethanol was added to the residueto give(S)-1-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(64.1 g) as a white solid.

[0184] (2) The above-mentioned compound (64.1 g) and sodium azide (11.8g) were dissolved in DMF (250 mL), and the mixture was stirred at 85° C.for 5 hr. The reaction mixture was added to water and the precipitatedcrystals were collected by filtration to give(S)-1-((2S,4S)-4-azido-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(50.1 g) as a white solid.

[0185] (3) The above-mentioned compound (50.1 g) was dissolved inethanol (500 mL). The mixture was stirred under a hydrogen atomosphere(1 atm) in the presence of 5% palladium/barium sulfate (5.9 g). Thereaction mixture was filtrated and the filtrate was concentrated underreduced pressure. Diethyl ether was added thereto and the precipitatedsolid was collected by filtration to give the title compound (45.5 g) asa white solid.

[0186]¹H-NMR(CDCl₃)δ1.23-1.52(10H,m), 1.60-2.47(8H,m), 2.86-3.00(1H,m),3.43-3.65(3H,m), 4.25-4.40(1H,m), 4.75-5.02(1H,m).

Reference Example 4

[0187] Synthesis of(2S,4R)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)aminopyrrolidine-2-carboxylicacid

[0188] (1) N-tert-Butoxycarbonyl-L-cis-4-hydroxyproline (24.5 g) andtriethylamine (15.4 mL) were dissolved in dichloromethane (500 mL).Methanesulfonyl chloride (8.1 mL) was added thereto under ice-cooling.After stirring at room temperature for 3 hr, the reaction mixture waswashed with water and dried. The solvent was evaporated under reducedpressure. The residue was dissolved in DMF (250 mL) and sodium azide(7.15 g) was added. The mixture was stirred at 80° C. for 3 hr, added towater and extracted with ethyl acetate. The extract was dried, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give methyl(2S,4R)-4-azido-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (18.4 g)as an oil.

[0189] (2) The above-mentioned compound (18.3 g) was dissolved inmethanol (200 mL), and the mixture was stirred under a hydrogenatomosphere (1 atm) in the presence of 5% palladium/carbon (5.9 g). Thereaction mixture was filtrated and the filtrate was concentrated underreduced pressure to give methyl(2S,4R)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (16.6 g)as an oil.

[0190] (3) The above-mentioned compound (3.32 g) and triethylamine (1.4mL) were dissolved in tetrahydrofuran (20 mL), and2-chloro-5-cyanopyridine (1.0 g) was added thereto. The mixture wasstirred at 80° C. for 4 hr. The reaction mixture was added to water andextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution and brine, and dried. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography to give methyl(2S,4R)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridylamino)pyrrolidine-2-carboxylate(1.2 g) as a white solid.

[0191] (4) The above-mentioned compound (0.94 g) was dissolved inmethanol (30 mL), and 1 mol/L aqueous sodium hydroxide solution (3.0 mL)was added thereto. The mixture was stirred at room temperature for 15hr. The reaction mixture was concentrated and 5% aqueous citric acidsolution was added to the residue. The mixture was extracted with ethylacetate, and the extract was washed with brine and dried. The solventwas evaporated under reduced pressure to give the title compound (0.75g) as amorphous.

[0192]¹H-NMR(CDCl₃)δ1.33-1.57(9H,m), 2.14-2.68(2H,m), 3.27-3.55(1H,m),3.82-4.00(1H,m), 4.33-4.57(2H,m), 6.23(1H,brs), 6.50(1H,d,J=8.7 Hz),7.64(1H,dd,J=8.7,2.1 Hz)8.33(1H,d,J=2.1 Hz).

Reference Example 5

[0193] Synthesis of(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid

[0194] (1) N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (20.7 g) andtriethylamine (15.4 mL) were dissolved in dichloromethane (400 mL).p-Toluenesulfonic acid chloride (16.8 g) was added thereto underice-cooling. After stirring at room temperature for 15 hr, the reactionmixture was washed with water and dried. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gelchromatography to give methyl(2S,4R)-1-tert-butoxycarbonyl-4-(p-toluenesulfonyloxy)pyrrolidine-2-carboxylate(11.7 g). (2) The above-mentioned compound (11.7 g) was dissolved in DMF(100 ML), and sodium azide (1.95 g) was added thereto. The mixture wasstirred at 80° C. for 3 hr. The reaction mixture was added to water, andextracted with ethyl acetate. The extract was dried, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give methyl(2S,4S)-4-azide-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (7.99 g)as an oil.

[0195] (3) The above-mentioned compound (7.99 g) was dissolved inmethanol (150 mL). The mixture was stirred under a hydrogen atomosphere(1 atm) in the presence of 10% palladium/carbon (2 g). The reactionmixture was filtrated and the filtrate was concentrated under reducedpressure to give methyl(2S,4S)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (7.23 g)as an oil.

[0196] (4) The above-mentioned compound (2.4 g) and triethylamine (1.4mL) were dissolved in tetrahydrofuran (20 mL), and 2-chlorobenzoxazole(0.82 mL) was added thereto. The mixture was stirred at 60° C. for 3 hr.The reaction mixture was added to water, and extracted with ethylacetate. The extract was ashed with saturated aqueous sodiumhydrogencarbonate solution and dried. The solvent was evaporated underreduced pressure and the residue was purified by silica gelchromatography to give methyl(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate(1.49 g) as amorphous.

[0197] (5) The above-mentioned compound (1.49 g) was dissolved inmethanol (50 mL), and 1 mol/L aqueous sodium hydroxide solution (5.0 mL)was added thereto. The mixture was stirred for 15 hr and concentrated.The residue was extracted with water and the extract was washed withethyl acetate. 5% Aqueous citric acid solution was added thereto to givethe title compound (1.39 g) as a white solid.

[0198]¹H-NMR(DMSO-d₆)δ1.28-1.50(9H,m), 1.93-2.08(1H,m), 2.53-2.75(1H,m),3.18-3.30(1H,m), 3.77-4.33(2H,m), 6.97-7.40(4H,m), 8.06-8.16(1H,m),12.63(1H,brs).

Reference Example 6

[0199] Synthesis of(2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid

[0200] (1) Methyl(2S,4R)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate [productof Reference Example 4(2), 3.32 g] and triethylamine (1.4 mL) weredissolved in tetrahydrofuran (20 mL). 2-Chlorobenzoxazole (0.86 mL) wasadded thereto and the mixture was stirred at room temperature for 48 hr.The reaction mixture was added to water and extracted with ethylacetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution and brine, and dried. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel chromatography to give methyl(2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate(1.48 g) as a white solid.

[0201] (2) The above-mentioned compound (1.31 g) was dissolved inmethanol (30 mL) and 1 mol/L aqueous sodium hydroxide solution (4.4 mL)was added thereto. The mixture was stirred at room temperature for 15 hrand the reaction mixture was concentrated. To the residue was added 5%aqueous citric acid solution and the mixture was extracted with ethylacetate. The extract was washed with brine and dried. The solvent wasevaporated under reduced pressure to give the title compound (1.11 g) asa white solid.

[0202]¹H-NMR(CDCl₃)δ1.32-1.68(9H,m), 2.20-2.80(2H,m), 3.37-3.62(1H,m),3.88-4.10(1H,m), 4.37-4.68(2H,m), 7.01-7.43(4H,m).

Reference Example 7

[0203] Synthesis of(2S,4S)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid

[0204] (1) Methyl(2S,4S)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate [productof Reference Example 5(3), 2.4 g] and triethylamine (2.0 mL) weredissolved in tetrahydrofuran (20 mi), and benzoyl chloride (1.1 mL) wasadded thereto. The mixture was stirred for 1 hr. The reaction mixturewas added to water and extracted with ethyl acetate. The extract waswashed with saturated aqueous sodium hydrogencarbonate solution anddried. The solvent was evaporated under reduced pressure and the residuewas purified by silica gel chromatography to give methyl(2S,4S)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate(1.63 g) as a white solid.

[0205] (2) The above-mentioned compound (1.5 g) was dissolved inmethanol (50 mL) and 1 mol/L aqueous sodium hydroxide solution (4.7 mL)was added thereto. The mixture was stirred for 15 hr. The reactionmixture was concentrated and 5% aqueous citric acid solution was addedto the residue. The mixture was extracted with ethyl acetate, and theextract was washed with brine and dried. The solvent was evaporatedunder reduced pressure to give the title compound (1.1 g) as amorphous.

Reference Example 8

[0206] Synthesis of(2S,4R)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid

[0207] (1) The product (3.32 g) of Reference Example 4(2) andtriethylamine (1.4 mL) were dissolved in tetrahydrofuran (20 mL), andbenzoyl chloride (0.87 mL) was added thereto. The mixture was stirredfor 1 hr. The reaction mixture was added to water and extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution and dried. The solvent was evaporated underreduced pressure and the residue was purified by silica gelchromatography to give methyl(2S,4R)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate(2.4 g) as amorphous.

[0208] (2) The above-mentioned compound (2.4 g) was dissolved inmethanol (80 mL), and 1 mol/L aqueous sodium hydroxide solution (8.2 mL)was added thereto. The mixture was stirred for 15 hr. The reactionmixture was concentrated and 5% aqueous citric acid solution was addedto the residue. The mixture was extracted with ethyl acetate, and theextract was washed with brine and dried. The solvent was evaporatedunder reduced pressure to give the title compound (1.9 g) as a whitesolid.

[0209]¹H-NMR(CDCl₃)δ1.33-1.55(9H,m), 2.12-2.75(2H,m), 3.31-3.60(1H,m),3.84-4.00(1H,m), 4.30-4.81(2H,m), 6.16-6.55(4H,m), 7.38-7.80(5H,m).

Reference Example 9

[0210] Synthesis of3-[(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine

[0211] N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (69.4 g) andthiazolidine (29.4 g) were dissolved-in DMF (300 mL), and HOBT (50.5 g)and EDC hydrochloride (63.3 g) were successively added thereto. Themixture was stirred at room temperature for hr and the reaction mixturewas concentrated. To the concentrate were added brine and saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was dried, and the solvent wasevaporated under reduced pressure to give the title compound (56.3 g) asa colorless transparent oil.

[0212]¹H-NMR(CDCl₃)δ1.41-1.45(9H,m), 1.95-2.34(2H,m)2.62-3.25(2H,m),3.40-3.98(4H,m),4.40-4.90(4H,m).

Reference Example 10

[0213] Synthesis of3-((2S,4S)-4-amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine

[0214] (1)3-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(title compound of Reference Example 9, 56.3 g) and triethylamine (28.5mL) were dissolved in dichloromethane (1.0 1), and methanesulfonylchloride (15.1 mL) was added thereto under ice-cooling. After stirringunder ice-cooling for 1 hr, the reaction mixture was washed with waterand dried. The solvent was evaporated under reduced pressure to give3-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(70.5 g) as. an oil.

[0215] (2) The above-mentioned compound (70.5 g) and sodium azide (13.3g) were dissolved in DMF (500 mL), and the mixture was stirred at 80° C.for 5 hr. The reaction mixture was concentrated under reduced pressureand water was added thereto. The mixture was extracted with ethylacetate, and the organic layer was dried and concentrated. The residuewas purified by silica gel chromatography to give3-((2S,4S)-4-azido-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(39.5 g) as a white solid.

[0216] (3) The above-mentioned compound (26.7 g) was dissolved inethanol (270 mL) and the mixture was stirred under a hydrogenatomosphere (1 atm) for 18 hr in the presence of 10% palladium carboncatalyst (13.4 g). The reaction mixture was filtrated and the filtratewas concentrated under reduced pressure to give the title compound (24.5g) as a black solid.

[0217]¹H-NMR(CDCl₃)δ1.40-1.45(9H,m), 1.70-1.83(1H,m), 2.07(2H,brs),2.32-2.56(1H,m), 2.90-3.19(2H,m), 3.25-3.58(2H,m), 3.60-4.14(3H,m),4.31-4.80(3H,m).

Reference Example 11

[0218] Synthesis of3-((2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(1) N-tert-Butoxycarbonyl-L-cis-4-tert-butyldimethylsilyloxyproline[product of Reference Example 1

[0219] (1), 5.55 g] and thiazolidine (1.4 mL) were dissolved in DMF (55mL), and triethylamine (2.24 mL), HOBT (2.96 g) and EDC hydrochloride(3.70 g) were successively added thereto. The mixture was stirred atroom temperature for 13 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution, and extracted with ethylacetate. The extract was washed with water and brine and dried. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(3.41 g) as a white solid.

[0220] (2) The above-mentioned compound (3.36 g) was dissolved intetrahydrofuran (50 mL), and a 1.0 mol/L solution (9 mL)tetrabutylammonium fluoride in tetrahydrofuran was added dropwise underice-cooling. The mixture was stirred at room temperature for 18 hr, andthe solvent was evaporated under reduced pressure. The residue was addedto brine and extracted with ethyl acetate. The extract was dried and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give the title compound (2.44 g) as awhite solid.

[0221]¹H-NMR(DMSO-d₆)δ1.25-1.45(9H,m), 1.52-1.70(1H,m), 2.35-2.50(1H,m),2.95-3.20(3H,m), 3.50-3.80(3H,m), 4.10-4.25(1H,m), 4.37-4.78(3H,m),5.18(1H,brs).

Reference Example 12

[0222] Synthesis of3-((S)-1-tert-butoxycarbonyl-4-oxo-2-yrrolidinylcarbonyl)-1,3-thiazolidine

[0223] The title compound (55.4 g) of Reference Example 9 andtriethylamine (46 mL) were dissolved in dichloromethane (350 mL). Asolution of sulfur trioxide pyridine complex (52.4 g) in dimethylsulfoxide (150 mL) was added thereto under ice-cooling, and the mixturewas stirred for 2 hr. Saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with brine anddried. The solvent was evaporated under reduced pressure and the residuewas purified by silica gel chromatography to give the title compound(30.3 g) as a white solid.

[0224]¹H-NMR(CDCl₃)δ1.47(9H,s), 2.45-2.57(1H,m), 2.70-2.93(1H,m),2.97-3.22(2H,m), 3.66-3.78(0.6H,m), 3.80-4.10(3H,m), 4.28-4.38(0.4H,m),4.45-5.08(3H,m).

Reference Example 13

[0225] Synthesis of(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolyl)pyrrolidine-2-carboxylic acid

[0226] (1) N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline benzyl ester(20.3 g) and triethylamine (17.6 mL) were dissolved in dichloromethane(120 mL), and a solution of sulfur trioxide pyridine complex (25.1 g) indimethyl sulfoxide (60 mL) was added thereto under ice-cooling, and themixture was stirred for 5 hr. Saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with brine anddried. The solvent was evaporated under reduced pressure and the residuewas purified by silica gel chromatography to give benzyl(S)-1-tert-butoxycarbonyl-4-oxopyrrolidine-2-carboxylate (9.76 g) as anoil.

[0227] (2) The above-mentioned compound (2.50 g), indoline (1.05 mL) andacetic acid (0.45 mL) were dissolved in 1,2-dichloroethane (40 mL), andsodium triacetoxyborohydride (3.32 g) was added hereto. The mixture wasstirred at room temperature for 6 hr and saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture. Themixture was extracted with ethyl acetate, and the extract was washedwith brine and dried. The solvent was evaporated under reduced pressureand the residue was purified by silica gel chromatography to give benzyl(2S-,4S)-1-tert-butoxycarbonyl-4-(1-indolinyl)pyrrolidine-2-carboxylate(2.59 g) as an oil.

[0228] (3) The above-mentioned compound (2.53 g) was dissolved inacetone (50 mL) and manganese dioxide (7.51 g) was added thereto. Themixture was stirred at room temperature for 12 hr and the reactionmixture was filtrated. The filtrate was concentrated under reducedpressure and the residue was purified by silica gel chromatography togive benzyl(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolyl)pyrrolidine-2-carboxylate(2.43 g) as an oil.

[0229] (4) The above-mentioned compound (2.42 g) was dissolved inmethanol (50 mL) and the mixture was stirred under a hydrogenatomosphere (1 atm) for 20 hr in the presence of 10% palladium/carbon(0.25 g). The reaction mixture was filtrated and the filtrate wasconcentrated under reduced pressure to give the title compound (1.91 g)as a pale-green solid.

[0230]¹H-NMR(CDCl₃)δ1.49(9H,s), 2.37-3.00(2H,m), 3.60-3.85(1H,m),4.05-4.25(1H,m), 4.40-4.60(1H,m), 4.95-5.10(1H,m), 6.54(1H,s),7.13(1H,t,J=7.7 Hz), 7.18-7.28(2H,m), 7.38(1H,d,J=8.2 Hz),7.62(1H,d,J=7.7 Hz).

Reference Example 14

[0231] Synthesis of1-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)pyrrolidine

[0232] (1) N-tert-Butoxycarbonyl-L-trans-4-hydroxyproline (46.25 g) andpyrrolidine (18 mL) were dissolved in DMF (200 mL), and HOBT (45.5 g)and EDC hydrochloride (46.0 g) were successively added thereto. Themixture was stirred at room temperature for 13 hr, and the solvent wasevaporated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure to give1-((2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)pyrrolidine(59.3 g) as an oil.

[0233] (2) The above-mentioned compound (59.3 g) and triethylamine (41mL) were dissolved in dichloromethane (350 mL), and a solution of sulfurtrioxide pyridine complex (46.5 g) in dimethyl sulfoxide (100 mL) wasadded thereto under ice-cooling. The mixture was stirred for 2 hr andsaturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture. The mixture was extracted with ethyl acetate, and theextract was washed with brine and dried. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give the title compound (11.9 g) as a white solid.

[0234]¹H-NMR(CDCl₃)δ1.47(9H,s), 1.80-2.08(4H,m), 2.42-2.53(1H,m),2.68-2.88(1H,m), 3.35-3.58(3H,m), 3.62-4.13(3H,m), 4.85(0.4H,d,J=9.0Hz), 4.99(0.6H,d,J=8.7 Hz).

Reference Example 15

[0235] Synthesis of3-((2S,4R)-4-amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine

[0236] (1) The title compound (13.6 g) of Reference Example 11 wasdissolved in dichloromethane (250 mL), and triethylamine (7 mL) wasadded thereto. Methanesulfonyl chloride. (3.64 mL) was added to thereaction mixture under ice-cooling, and the mixture was stirred for 1hr. Water was added to the reaction mixture and the organic layer wasseparated. The solvent was evaporated under reduced pressure and theresidue was dissolved in DMF (200 mL). Sodium azide (3.25 g) was addedthereto and he mixture was stirred at 85° C. for 3 hr with heating. Thereaction mixture was concentrated under reduced pressure and water wasadded to the residue. The mixture was extracted with ethyl acetate andthe extract was concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give3-((2S,4R)-4-azido-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(9.9 g).

[0237] (2) The above-mentioned compound (9.9 g) was dissolved in ethanol(150 mL) and the mixture was stirred at room temperature for 18 hr undera hydrogen atomosphere (1 atm) in the presence of 10% palladium/carbon(10 g). The reaction mixture was filtrated and the filtrate wasconcentrated under reduced pressure to give the title compound (10.1 g)as a black solid.

[0238]¹H-NMR(500MHz,DMSO-d₆)δ1.30(4.5H,s), 1.38(4.5H,s),1.42-1.52(1H,m), 2.05(2H,brs), 2.33-2.45(1H,m), 2.92-3.88(7H,m),4.37-4.72(3H,m).

Example 1

[0239] Synthesis of(S)-2-cyano-1-((2S,4S)-4-hydroxy-2-pyrrolidinylcarbonyl)pyrrolidinetrifluoroacetate

[0240](S)-1-((2S,4S)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(title compound of Reference Example 1, 544 mg) was dissolved indichloromethane (18 mL), and trifluoroacetic acid (1.8 mL) was addedthereto. The mixture was stirred at room temperature for 18 hr, and thesolvent was evaporated under reduced pressure. Ethanol and diethyl etherwere added to the residue and the precipitated powder was collected byfiltration to give the title compound (350 mg) as powdery whitecrystals.

[0241]¹H-NMR(DMSO-d₆)δ1.68-2.85(6H,m), 3.10-3.30(2H,m), 3.44-3.70(2H,m),4.30-4.60(2H,m), 4.78-5.09(1H,m), 5.35-5.50(1H,m), 9.18(2H,brs).

Example 2

[0242] Synthesis of(S)-2-cyano-1-((2S,4R)-4-hydroxy-2-pyrrolidinylcarbonyl)pyrrolidinehydrochloride

[0243] The title compound (309 mg) of Reference Example 2 was dissolvedin 4 mol/L hydrochloric acid-1,4-dioxane (2 mL), and the mixture wasstirred at room temperature for 18 hr. The solvent was evaporated underreduced pressure and the residue was purified by HPLC to give the titlecompound (36 mg) as powdery white crystals.

[0244]¹H-NMR(DMSO-d₆)δ1.85-2.44(6H,m), 3.05-3.72(4H,m), 4.41-4.60(2H,m),4.78-5.16(1H,m), 5.55-5.70(1H,m).

Example 3

[0245] Synthesis of(S)-1-((2S,4S)-4-amino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidinedihydrochloride

[0246](S)-1-((2S,4S)-4-Amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(title compound of Reference Example 3, 308 mg) was dissolved in 4 mol/Lhydrochloric acid-1,4-dioxane (1.25 mL), and the mixture was stirred atroom temperature for 27 hr. The solvent was evaporated under reducedpressure and tetrahydrofuran was added thereto. The precipitated solidwas collected by filtration to give the title compound (214 mg).

[0247]¹H-NMR(DMSO-d₆)δ1.85-2.35(5H,m), 2.80-2.93(1H,m), 3.27-3.68(4H,m),3.83-3.98(1H,m), 4.52-4.64(1H,m), 4.84(1H,d,J=4.5,7.8 Hz), 8.81(3H,brs).

Example 4

[0248] Synthesis of(S)-1-((2S,4S)-4-anilino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidinetrifluoroacetate

[0249] (1) The title compound (6.18 g) of Reference Example 2 andtriethylamine (8.4 mL) were dissolved in dimethyl sulfoxide (15 mL).Sulfur trioxide pyridine complex (9.54 g) was added thereto. Afterstirring at room temperature for 1 hr, water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with water and dried. The solvent was evaporated underreduced pressure and the residue was purified by silica gelchromatography to give(S)-1-((2S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(6.0 g) as an oil.

[0250] (2) The above-mentioned compound (1.5 g) and aniline (0.43 mL)were dissolved in methanol (25 mL), and the mixture was stirred at roomtemperature for 6 hr in the presence of molecular sieve 3A (1.5 g).Sodium cyanoborohydride (0.315 g) and acetic acid (0.4 mL) were added tothe reaction mixture, and the mixture was stirred for 1 hr. The reactionmixture was filtrated and the filtrate was evaporated under reducedpressure. Saturated aqueous sodium hydrogencarbonate solution was addedto the residue, and the mixture was extracted with ethyl acetate. Theextract was dried, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography to give(S)-1-((2S,4S)-4-anilino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(0.74 g) as amorphous.

[0251] (3) The above-mentioned compound (0.82 g) was dissolved indichloromethane (21 mL) and trifluoroacetic acid (2.1 mL) was addedthereto. The mixture was stood at room temperature for 15 hr, and thesolvent was evaporated under reduced pressure. The residue was purifiedby HPLC and freeze-dried to give the title compound (0.246 g) asamorphous.

[0252]¹H-NMR(DMSO-d₆)δ1.52-2.33(5H,m), 2.87-3.22(2H,m), 3.75-5.13(8H,m),6.50-6.67(3H,m), 7.03-7.20(2H,m), 8.91(1H,brs), 9.88(1H,brs).

Example 5

[0253] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-nitrophenyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0254] (1) The title compound (0.924 g) of Reference Example 3,diisopropylethylamine (1.7 mL) and 4-fluoronitrobenzene (0.53 mL) weredissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture was stirredat 80° C. for 15 hr,. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was dried, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(1.14 g) as amorphous.

[0255] (2) The above-mentioned compound (1.13 g) was dissolved in ethylacetate (3.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (3.4 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated solid was collected by filtration to give the titlecompound (0.67 g).

[0256]¹H-NMR(DMSO-d₆)δ1.74-2.37(6H,m), 2.90-3.10(1H,m), 3.27-3.97(3H,m),4.37-4.70(2H,m), 4.80-5.20(1H,m), 6.90-7.34(2H,m), 7.88-8.03(2H,m),9.09(1H,brs), 10.98(1H,brs).

Example 6

[0257] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0258] (1) The title compound (924 mg) of Reference Example 3,diisopropylethylamine (1.7 mL) and 4-fluorobenzonitrile (606 mg) weredissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture was stirredat 100° C. for 15 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was dried and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give(S)-2-cyano-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]pyrrolidine(340 mg) as amorphous.

[0259] (2) The above-mentioned compound (420 mg) was dissolved in ethylacetate (1.2 mL), and 4 mol/L hydrochloric acid-ethyl acetate (1.2 mL)was added thereto. The mixture was stood at room temperature for 15 hrand the precipitated solid was collected by filtration to give the titlecompound (289 mg).

[0260]¹H-NMR(DMSO-d₆)δ1.62-1.80(1H,m), 1.97-2.33(4H,m), 2.90-3.24(2H,m),3.64-3.96(3H,m), 4.20-4.63(2H,m), 4.80-5.13(1H,m), 6.70(2H,d,J=8.7 Hz),7.53(2H,d,J=8.7 Hz), 9.00(1H,brs), 10.50(1H,brs).

Example 7

[0261] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0262] (1) The title compound (924 mg) of Reference Example 3,diisopropylethylamine (1.7 mL) and 2-fluorobenzonitrile (0.54 mL) weredissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture was stirredat 100° C. for 15 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was dried and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(177 mg) as amorphous.

[0263] (2) The above-mentioned compound (115 mg) was dissolved in ethylacetate (0.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (0.35 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated solid was collected by filtration to give the titlecompound (46 mg).

[0264]¹H-NMR(DMSO-d₆),1.70-2.36(6H,m), 2.93-3.74(3H,m), 4.28-4.66(2H,m),4.81-5.15(1H,m), 6.33(1H,d,J=8.1 Hz), 6.77(1H,dd,J=8.4,8.1 Hz),6.90(1H,d,J=8.4 Hz), 7.39-7.60(2H,m).

Example 8

[0265] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(2-fluoro-4-nitrophenyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0266] (1) The title compound (0.924 g) of Reference Example 3,diisopropylethylamine (1.7 mL) and 3,4-difluoronitrobenzene (0.55 mL)were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture wasstirred at 80° C. for 15 hr. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The extract was dried andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-fluoro-4-nitrophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.95 g) as amorphous.

[0267] (2) The above-mentioned compound (0.95 g) was dissolved in ethylacetate (3 mL), and 4 mol/L hydrochloric acid-ethyl acetate (2.65 mL)was added thereto. The mixture was stood at room temperature for 15 hrand the precipitated solid was collected by filtration to give the titlecompound (0.63 g).

[0268]¹H-NMR(DMSO-d₆)δ1.74-2.37(6H,m), 2.90-3.10(1H,m), 3.27-3.97(3H,m),4.37-4.70(2H,m), 4.80-5.20(1H,m), 6.90-7.34(2H,m), 7.88-8.03(2H,m),9.09(1H,brs), 10.98(1H,brs).

Example 9

[0269] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-cyano-2-fluorophenyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0270] (1) The title compound (924 mg) of-Reference Example 3,diisopropylethylamine (1.7 mL) and 3,4-difluorobenzonitrile (700 mg)were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture wasstirred at 80° C. for 15 hr. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The extract was dried andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyano-2-fluorophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(920 mg) as amorphous.

[0271] (2) The above-mentioned compound (920 mg) was dissolved in ethylacetate (2.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (2.2 mL)was added thereto. The mixture was stood at room temperature for 15 hrand the precipitated solid was collected by filtration to give the titlecompound (756 mg).

[0272]¹H-NMR(DMSO-d₆)δ1.67-2.35(6H,m), 2.88-3.06(1H,m), 3.22-3.73(3H,m),4.27-4.64(2H,m), 4.86-5.13(1H,m), 6.73(1H,d,J=6.3 Hz), 7.82-7.92(1H,m),7.51(1H,dd,J=8.4,1.5 Hz), 7.61(1H,dd,J=12.0,1.5 Hz), 8.98(1H,brs),10.75(1H,brs).

Example 10

[0273] Synthesis of(S)-1-[(2S,4S)-4-(4-bromo-2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinehydrochloride

[0274] (1) The title compound (924 mg) of Reference Example 3,diisopropylethylamine (1.7 mL) and 3-bromo-6-fluorobenzonitrile (1000mg) were dissolved in N-methyl-2-pyrrolidone (10 mL) and the mixture wasstirred at 80° C. for 5 hr. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The extract was dried andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-bromo-2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(904 mg) as amorphous.

[0275] (2) The above-mentioned compound (900 mg) was dissolved in ethylacetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.8 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr andthe precipitated solid was collected by filtration to give the titlecompound (501 mg).

[0276]¹H-NMR(DMSO-d₆)δ1.70-2.34(4H,m), 2.93-3.07(1H,m), 3.42-3.65(3H,m),4.33-4.61(2H,m), 4.82-5.10(1H,m), 6.56(1H,d,J=8.7 Hz),6.94(1H,dd,J=8.1,1.8 Hz), 7.12(1H,d,J=1.8 Hz), 7.49(1H,d,J=8.1 Hz),8.96(1H,brs), 10.02(1H,brs).

Example 11

[0277] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(3,4-dicyanophenyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0278] (1) The title compound (0.924 g) of Reference Example 3,diisopropylethylamine (1.7 mL) and 3-fluorophthalonitrile (0.73 g) weredissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture was stirredat 80° C. for 4 hr. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was dried and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3,4-dicyanophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(1.05 g) as amorphous.

[0279] (2) The above-mentioned compound (1.04 g) was dissolved in ethylacetate (5 mL) and 4 mol/L hydrochloric acid-ethyl acetate (3.0 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr andthe precipitated solid was collected by filtration to give the titlecompound (0.794 g).

[0280]¹H-NMR(DMSO-d₆)δ1.62-1.79(1H,m), 1.95-2.35(3H,m), 2.90-3.28(2H,m),3.53-3.71 (2H,m), 4.23-4.64(2H,m), 4.80-5.13(1H,m), 7.01(1H,dd,J=9.0,2.4Hz), 7.24(1H,d,J=2.4 Hz), 7.65(1H,d,J=6.3 Hz), 7.78(1H,d,J=9.0 Hz),9.06(1H,brs), 10.62(1H,brs).

Example 12

[0281] Synthesis of(S)-1-[(2S,4S)-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinehydrochloride (1) The title compound (0.924 g) of Reference Example 3,diisopropylethylamine (1.7 mL) and 2-chloro-4-fluorobenzonitrile (0.78g) were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture wasstirred at 80° C. for 4 hr. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The extract was dried andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.94 g) as amorphous.

[0282] (2) The above-mentioned compound (0.93 g) was dissolved in ethylacetate (3 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.6 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr andthe precipitated solid was collected by filtration to give the titlecompound (0.73 g).

[0283]¹H-NMR(DMSO-d₆)δ1.58-1.80(1H,m), 1.96-2.37(3H,m), 2.92-3.22(2H,m),3.53-3.67(2H,m), 4.22-4.60(2H,m), 4.80-5.10(1H,m), 6.67(1H,dd,J=8.7,2.4Hz), 6.84(1H,d,J=2.4 Hz), 7.24(1H,d,J=6.9 Hz), 7.61(1H,d,J=8.7 Hz),9.02(1H,brs), 9.97(1H,brs).

Example 13

[0284] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-cyano-2,6-difluorophenyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0285] (1) The title compound (0.924 g) of Reference Example 3,diisopropylethylamine (1.7 mL) and 3,4,5-trifluorobenzonitrile (0.79 g)were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture wasstirred at 80° C. for 3 hr. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The extract was dried andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyano-2,6-difluorophenyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(1.08 g) as amorphous.

[0286] (2) The above-mentioned compound (1.08 g) was dissolved in ethylacetate (3 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.4 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr andthe precipitated solid was collected by filtration to give the titlecompound (0.706 g).

[0287]¹H-NMR(DMSO-d₆)δ1.72-2.33(6H,m), 2.77-2.92(1H,m), 3.20-3.70(3H,m),4.42-5.09(3H,m), 6.38(1H,d,J=8.4 Hz), 7.51-7.70(2H,m), 8.97(1H,brs),10.73(1H,brs).

Example 14

[0288] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(3-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinetrifluoroacetate

[0289] (1) The title compound (1.86 g) of Reference Example 3,diisopropylethylamine (3.14 mL) and 2-chloro-3-trifluoromethylpyridine(1.09 g) were dissolved in N-methyl-2-pyrrolidone (36 mL), and themixture was stirred at 120° C. for 8 hr. The reaction mixture was addedto saturated aqueous sodium hydrogencarbonate solution, and the mixturewas extracted with ethyl acetate. The extract was dried and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.099 g).

[0290] (2) The above-mentioned compound (99 mg) was dissolved indichloromethane (2.2 mL) and trifluoroacetic acid (0.2 mL) was addedthereto. The mixture was stood at room temperature for 18 hr. Thereaction mixture was concentrated under reduced pressure and purified byHPLC to give the title compound (3.2 mg) as amorphous.

[0291]¹H-NMR(DMSO-d₆)δ1.80-2.40(5H,m), 2.80-2.98(1H,m), 3.30-3.65(4H,m),4.40-4.78(1H,m), 4.80-4.89(1H,m), 4.90-5.10(1H,m), 6.58(1H,d,J=7.8 Hz),6.73-6.89(1H,m), 7.86(1H,d,J=6.6 Hz), 8.33(1H,d,J=3.9 Hz), 8.84(1H,brs),9.56(1H,brs).

Example 15

[0292] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(3-nitro-2-pyridyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinetrifluoroacetate

[0293] (1) The title compound (928 mg) of Reference Example 3,diisopropylethylamine (1.57 mL) and 2-chloro-3-nitropyridine (476 mg)were dissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture wasstirred at 80° C. for 3 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-nitro-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(851 mg) as a yellow oil.

[0294] (2) The above-mentioned compound (851 mg) was dissolved indichloromethane (20 mL) and trifluoroacetic acid (2.0 mL) was addedthereto. The mixture was stood at room temperature for 18 hr. Thereaction mixture was concentrated under reduced pressure and diethylether was added to the residue. The precipitated product was collectedby filtration to give a yellow powder (677 mg). This powder (257 mg) waspurified by HPLC to give the title compound (152 mg) as a yellow powder.

[0295]¹H-NMR(DMSO-d₆)δ1.89-2.37(5H,m), 2.86-3.04(1H,m), 3.38-3.65(4H,m),4.49-4.70(1H,m), 4.79-4.90(1H,m), 5.00-5.22(1H,m), 6.88(1H,dd,J=8.4,4.8Hz), 8.38-8.60(3H,m), 9.03(1H,brs), 9.73(1H,brs).

Example 16

[0296] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(3-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0297] (1) The title compound (1.86 g) of Reference Example 3,diisopropylethylamine (3.14 mL) and 2-chloro-3-cyanopyridine (0.831 g)were dissolved in N-methyl-2-pyrrolidone (36 mL), and the mixture wasstirred at 100° C. for 9 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.487 g).

[0298] (2) The above-mentioned compound (0.464 g) was dissolved in ethylacetate (1.13 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.41 mL)was added thereto. The mixture was stood at room temperature for 3 hr.The precipitated solid was collected by filtration to give the titlecompound (0.370 g) as a pale-brown powder.

[0299]¹H-NMR(DMSO-d₆)δ1.72-2.31(5H,m), 2.81-2.98(1H,m), 3.20-3.36(1H,m),3.40-3.69(3H,m), 4.45-4.67(1H,m), 4.75-5.11(1H,m), 6.78(1H,dd,J=7.5,4.8Hz), 7.35(1H,d,J=7.5 Hz), 7.99(1H,dd,J=7.5,1.8 Hz), 8.33(1H,dd,J=5.1,1.8Hz), 8.88(1H,brs), 10.50(1H,brs).

Example 17

[0300] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinetrifluoroacetate

[0301] (1) The title compound (928 mg) of Reference Example 3,diisopropylethylamine (1.57 mL) and 2-chloro-4-cyanopyridine (416 mg)were dissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture wasstirred at 120° C. for 18 hr. The reaction mixture was added tosaturated aqueous sodium hydrogencarbonate solution, and extracted withethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure.

[0302] The residue was purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(134 mg).

[0303] (2) The above-mentioned compound (134 mg) was dissolved indichloromethane (3.3 mL) and trifluoroacetic acid (0.3 mL) was addedthereto. The mixture was stirred at room temperature for 18 hr. Thereaction mixture was concentrated under reduced pressure and diethylether was added to the residue. The precipitated product was collectedby filtration to give a pale-brown powder (64 mg). This powder (64 mg)was purified by HPLC to give the title compound (8 mg) as a white solid.

[0304]¹H-NMR(DMSO-d₆)δ1.64-1.86(1H,m), 1.86-2.37(4H,m), 2.80-3.00(1H,m),3.06-3.28(1H,m), 3.42-3.69(3H,m), 4.42-4.70(2H,m), 4.75-5.10(1H,m),6.89(1H,s), 6.93(1H,d,J=5.2 Hz), 7.44(1H,d,J=6.2 Hz), 8.23(1H,d,J=4.7Hz), 8.96(1H,brs), 9.81(1H,brs).

Example 18

[0305] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinedihydrochloride

[0306] (1) The title compound (462 mg) of Reference Example 3,triethylamine (0.42 mL) and 2-chloro-5-cyanopyridine (210 mg) weredissolved in DMF (10 mL), and the mixture was stirred at 90° C. for 24hr. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure.

[0307] The residue was purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(310 mg) as amorphous.

[0308] (2) The above-mentioned compound (310 mg) was dissolved intetrahydrofuran (3 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2mL) was added thereto. The mixture was stood at room temperature for 15hr and the solvent was evaporated under reduced pressure. The residuewas purified by HPLC and freeze-dried to give the title compound (150mg) as amorphous.

[0309]¹H-NMR(DMSO-d₆)δ1.77-2.33(2.81-3.23(2H,m), 4.00-5.15(6H,m),6.61(1H,d,J=8.7 Hz), 7.77(1H,d,J=8.7 Hz), 7.91(1H,d,J=6.0 Hz),8.46(1H,s), 8.98(1H,brs), 9.91(1H,brs).

Example 19

[0310] Synthesis of(S)-1-[(2S,4R)-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinedihydrochloride

[0311] (1)(2S,4R)-1-tert-Butoxycarbonyl-4-(5-cyano-2-pyridyl)aminopyrrolidine-2-carboxylicacid (title compound of Reference Example 4, 0.73 g) and(S)-2-cyanopyrrolidine hydrochloride (0.29 g) were dissolved in DMF (10mL), and triethylamine (0.62 mL), HOBT (0.34 g) and EDC hydrochloride(0.42 g) were successively added thereto. The mixture was stirred atroom temperature for 15 hr. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The extract was dried andevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (0.58 g) as amorphous.

[0312] (2) The above-mentioned compound (0.57 g) was dissolved in 4mol/L hydrochloric acid-1,4-dioxane (4 mL), and the mixture was stood atroom temperature for 15 hr. The solvent was evaporated under reducedpressure, and the residue was purified by HPLC and freeze-dried to givethe title compound (0.181 g) as amorphous.

[0313]¹H-NMR(DMSO-d₆)δ1.93-2.68(6H,m), 3.13-3.70(4H,m), 4.58-5.10(3H,m),6.61(1H,d,J=8.7 Hz), 7.79(1H,dd,J=8.7,1.8 Hz), 7.98(1H,brs),8.48(1H,d,J=1.8 Hz), 8.87(1H,brs), 9.78(1H,brs).

Example 20

[0314] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]pyrrolidine2 trifluoroacetate

[0315] (1) The title compound (0.924 g) of Reference Example 3,diisopropylethylamine (1.7 mL) and 2-chloro-5-trifluoromethylpyridine(0.54 g) were dissolved in N-methyl-2-pyrrolidone (10 mL), and themixture was stirred at 120° C. for 8 hr. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The extractwas dried and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.40 g) as amorphous.

[0316] (2) The above-mentioned compound (0.40 g) was dissolved indichloromethane (9 mL) and trifluoroacetic acid (0.9 mL) was addedthereto. The mixture was stood at room temperature for hr, and thesolvent was evaporated under reduced pressure. The residue was purifiedby HPLC and freeze-dried to give the title compound (0.163 g) asamorphous.

[0317]¹H-NMR(DMSO-d₆)δ1.68-2.32(5H,m), 2.85-3.26(2H,m), 4.38-5.12(8H,m),6.65(1H,d,J=9.0 Hz), 7.66(1H,d,J=6.3 Hz), 7.72(1H,dd,J=9.0,2.4 Hz),8.35(1H,s), 8.96(1H,brs), 9.80(1H,brs).

Example 21

[0318] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(5-nitro-2-pyridyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinedihydrochloride

[0319] (1) The title compound (0.462 g) of Reference Example 3,triethylamine (0.42 mL) and 2-chloro-5-nitropyridine (0.24 g) weredissolved in DMF (6 mL), and the mixture was stirred at 100° C. for 8hr. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-nitro-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.50 g) as amorphous.

[0320] (2) The above-mentioned compound (0.50 g) was dissolved intetrahydrofuran (3 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (3 mL)was added thereto. The mixture was stood at room temperature for 15 hrand the precipitated solid was collected by filtration to give the titlecompound (0.445 g).

[0321]¹H-NMR(DMSO-₆)δ1.69-2.37(5H,m), 2.80-3.26(2H,m), 3.47-3.76(3H,m),4.50-5.15(3H,m), 6.67(1H,d,J=9.3 Hz), 8.18(1H,dd,J=9.3,3.0 Hz),8.58(1H,s), 8.90-9.12(2H,m), 10.65(1H,brs).

Example 22

[0322] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(3,5-dinitro-2-pyridyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinetrifluoroacetate

[0323] (1) The title compound (0.928 g) of Reference Example 3,diisopropylethylamine (1.57 mL) and 2-chloro-3,5-dinitropyridine (0.611g) were dissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was added tosaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3,5-dinitro-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(1.21 g) as a yellow oil.

[0324] (2) The above-mentioned compound (1.18 g) was dissolved indichloromethane (25 mL) and trifluoroacetic acid (2.5 mL) was addedthereto. The mixture was stirred at room temperature for 18 hr. Thereaction mixture was concentrated under reduced pressure and diethylether was added to the residue. The precipitated yellow powder wascollected by filtration to give the title compound (1.12 g).

[0325]¹H-NMR(DMSO-d₆)δ1.68-2.33(5H,m), 2.84-3.08(1H,m), 3.32-3.68(4H,m),4.49-4.70(1H,m), 4.76-4.90(1H,m), 5.11-5.37(1H,m), 9.01(1H,s),9.04(1H,brs), 9.25(1H,brs), 9.28(1H,s), 9.84(1H,brs).

Example 23

[0326] Synthesis of(S)-1-[(2S,4S)-4-(6-chloro-3-pyridazinyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinehydrochloride

[0327] (1) The title compound (928 mg) of Reference Example 3,diisopropylethylamine (1.57 mL) and 2,6-dichloropyridazine (447 mg) weredissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture was stirredat 120° C. for 5 hr. The reaction mixture was added to saturated aqueoussodium hydrogencarbonate solution, and the mixture was extracted withethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(6-chloro-3-pyridazinyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(58 mg).

[0328] (2) The above-mentioned compound (57 mg) was dissolved in ethylacetate (1.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.2 mL)was added thereto. The mixture was stood at room temperature for 4 hrand the precipitated solid was collected by filtration to give the titlecompound (31 mg).

[0329]¹H-NMR(DMSO-d₆)δ11.69-2.35(5H,m), 2.88-3.01(1H,m),3.09-3.29(1H,m), 3.50-3.70(3H,m), 4.50-4.72(2H,m), 4.76-5.15(1H,m),7.00(1H,d,J=9.3 Hz), 7.48(1H,d,J=9.3 Hz), 7.71(1H,brs), 9.00(1H,brs),10.31(1H,brs).

Example 24

[0330] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(2-pyrimidinyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0331] (1) The title compound (1.85 g) of Reference Example 3,diisopropylethylamine (3.14 mL) and 2-chloropyrimidine (0.687 g) weredissolved in N-methyl-2-pyrrolidone (30 mL), and the mixture was stirredat 100° C. for 24 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution, and extracted with ethylacetate. The extract was dried and the solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatographyto give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-pyrimidinyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.950 g) as a pale-brown powder.

[0332] (2) The above-mentioned compound (0.833 g) was dissolved in ethylacetate (2.16 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.69 mL)was added thereto. The mixture was stood at room temperature for 18 hr.The precipitated solid was collected by filtration to give the titlecompound (0.626 g).

[0333]¹H-NMR(DMSO-d₆)δ1.70-2.35(5H,m), 2.80-2.95(1H,m), 3.10-3.30(1H,m),3.42-3.90(3H,m), 4.49-4.73(2H,m), 4.80-5.14(1H,m), 6.74(1H,t,J=5.1 Hz),7.67(1H,brs), 8.38(2H,d,J=5.1 Hz), 8.89(1H,brs), 10.37(1H,brs).

Example 25

[0334] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-trifluoromethyl-2-pyrimidinyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0335] (1) The title compound (1.85 g) of Reference Example 3,diisopropylethylamine (3.14 mL) and 2-chloro-4-trifluoromethylpyrimidine(1.10 g) were dissolved in N-methyl-2-pyrrolidone (30 mL), and themixture was stirred at room temperature for 18 hr. The reaction mixturewas added to saturated aqueous sodium hydrogencarbonate solution, andthe mixture was extracted with ethyl acetate. The extract was dried andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-trifluoromethyl-2-pyrimidinyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(2.44 g).

[0336] (2) The above-mentioned compound (2.27 g) was dissolved in ethylacetate (4.99 mL) and 4 mol/L hydrochloric acid-ethyl acetate (6.24 mL)was added thereto. The mixture was stood at room temperature for 4 hr.The precipitated solid was collected by filtration to give the titlecompound (1.94 g).

[0337]¹H-NMR(DMSO-d₆)δ1.72-2.35(5H,m), 2.78-2.99(1H,m), 3.10-3.30(1H,m),3.36-3.88(3H,m), 4.47-4.72(2H,m), 4.79-5.13(1H,m), 7.11(1H,d,J=5.1 Hz),8.20(1H,brs), 8.69(1H,d,J=4.2 Hz), 8.94(1H,brs), 10.73(1H,brs).

Example 26

[0338] Synthesis of(S)-1-[(2S,4S)-4-(2-benzoxazolyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinehydrochloride

[0339] (1)(2S,4S)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid (title compound of Reference Example 5, 1.04 g) and(S)-2-cyanopyrrolidine hydrochloride (0.40 g) were dissolved in DMF (5mL), and triethylamine (0.84 mL), HOBT (0.51 g) and EDC hydrochloride(0.63 g) were successively added thereto. The mixture was stirred atroom temperature for 15 hr. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was dried andevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]1-2-cyanopyrrolidine(0.86 g) as amorphous.

[0340] (2) The above-mentioned compound (0.86 g) was dissolved in 4mol/L hydrochloric acid-1,4-dioxane (6 mL), and the mixture was stood atroom temperature for 15 hr. The precipitated white solid was collectedby filtration to give the title compound (0.828 g).

[0341]¹H-NMR(DMSO-d₆)δ1.70-2.36(5H,m), 2.87-3.50(2H,m), 4.20-5.15(3H,m),7.00-7.49(4H,m), 8.24-8.38(1H,m), 8.97(1H,brs), 10.26(1H,brs).

Example 27

[0342] Synthesis of(S)-1-[(2S,4R)-4-(2-benzoxazolyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinehydrochloride

[0343] (1)(2S,4R)-4-(2-Benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid (title compound of Reference Example 6, 1.0 g) and(S)-2-cyanopyrrolidine hydrochloride (0.38 g) were dissolved in DMF (10mL), and triethylamine (0.81 mL), HOBT (0.49 g) and EDC hydrochloride(0.61 g) were successively added thereto. The mixture was stirred atroom temperature for 15 hr. Water was added to the reaction mixture, andmixture was extracted with ethyl acetate. The extract was dried and theresidue was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give(S)-1-[(2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.91 g) as amorphous.

[0344] (2) The above-mentioned compound (0.91 g) was dissolved in 4mol/L hydrochloric acid-1,4-dioxane (6 mL), and the mixture was stood atroom temperature for 15 hr. The precipitated white solid was collectedby filtration to give the title compound (0.841 g).

[0345]¹H-NMR(DMSO-d₆)δ1.93-2.73(6H,m), 3.30-3.94(4H,m), 4.36-5.18(3H,m),6.96-7.50(4H,m), 8.42-9.05(2H,m), 10.17(1H,brs).

Example 28

[0346] Synthesis of(S)-1-[(2S,4S)-4-(4-chlorophenylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinedihydrochloride

[0347] (1) The title compound (1.54 g) of Reference Example 3 and4-chlorobenzaldehyde (0.703 g) were dissolved in methanol (15 mL), andthe mixture was stirred at room temperature for 1 hr. Sodiumcyanoborohydride (0.315 g) and acetic acid (0.4 mL) were added to thereaction mixture, and the mixture was stirred for 1 hr. The reactionmixture was filtrated and the filtrate was evaporated under reducedpressure. Saturated aqueous sodium hydrogencarbonate solution was addedto the residue, and the mixture was extracted with ethyl acetate. Theextract was dried and the solvent was evaporated under reduced pressure.

[0348] The residue was purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-chlorophenylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(1.67 g) as amorphous.

[0349] (2) The above-mentioned compound (0.643 g) was dissolved in ethylacetate (1.9 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.9 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated solid was collected by filtration to give the titlecompound (0.62 g).

[0350]¹H-NMR(DMSO-d₆)δ2.00-2.37(5H,m), 2.90-3.05(1H,m), 3.52-3.73(4H,m),3.86-4.04(1H,m), 4.24(2H,s), 4.48-4.54(1H,m), 4.80-5.17(1H,m),7.53(2H,d,J=8.4 Hz), 7.66(2H,d,J=8.4 Hz), 9.07(1H,brs), 10.20(2H,brs),10.72(1H,brs).

Example 29

[0351] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-nitrophenylmethyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinedihydrochloride

[0352] (1) The title compound (1.54 g) of Reference Example 3 and4-nitrobenzaldehyde (6.801 g) were dissolved in methanol (15 mL), andthe mixture was stirred at room temperature for 1 hr. Sodiumcyanoborohydride (0.315 g) and acetic acid (0.4 mL) were added to thereaction mixture, and the mixture was stirred for 1 hr. The reactionmixture was filtrated and the filtrate was evaporated under reducedpressure. Saturated aqueous sodium hydrogencarbonate solution was addedto the residue and the mixture was extracted with chloroform. Theextract was dried and the solvent was evaporated under reduced pressure.The residue was purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrophenylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(1.15 g) as amorphous.

[0353] (2) The above-mentioned compound (1.15 g) was dissolved in ethylacetate (3 mL) and 4 mol/L hydrochloric acid-ethyl acetate (3.3 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr. Theprecipitated solid was collected by filtration to give the titlecompound (0.975 g).

[0354]¹H-NMR(DMSO-d₆)δ1.96-2.37(5H,m), 2.93-3.07(1H,m), 3.66-3.75(3H,m),3.93-4.10(1H,m), 4.40(2H,s), 4.50-4.67(1H,m), 4.80-5.17(1H,m),7.92(2H,d,J=8.7 Hz), 8.31(2H,d,J=8.7 Hz), 9.10(1H,brs),10.10-11.30(2H,m).

Example 30

[0355] Synthesis of(S)-2-cyano-1-[(2S,4s)-4-(4-phenoxyphenylmethyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinedihydrochloride

[0356] (1) The title compound (0.924 g) of Reference Example 3 and4-phenoxybenzaldehyde (0.594 g) were dissolved in methanol (15 mL), andthe mixture was stirred at room temperature for 1 hr. Sodiumcyanoborohydride (0.189 g) and acetic acid (0.2 mL) were added to thereaction mixture, and the mixture was stirred for 1 hr. The reactionmixture was evaporated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-phenoxyphenylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(0.99 g) as amorphous.

[0357] (2) The above-mentioned compound (0.99 g) was dissolved in ethylacetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.5 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr. Theprecipitated solid was collected by filtration to give the titlecompound (0.95 g).

[0358]¹H-NMR(DMSO-d₆)δ1.95-2.38(5H,m), 2.90-3.16(1H,m), 3.40-3.70(4H,m),3.89-4.03(1H,m), 4.21(2H,s), 4.50-4.67(1H,m), 4.80-5.17(1H,m),6.94-7.22(5H,m), 7.34-7.48(2H,m), 7.64(2H,d,J=8.4 Hz), 9.10(1H,brs),10.17(2H,brs), 10.90(1H,brs).

Example 31

[0359] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinedihydrochloride

[0360] (1) The title compound (924 mg) of Reference Example 3 and4-cyanobenzaldehyde (589 mg) were dissolved in methanol (15 mL), and themixture was stirred at room temperature for 1 hr. Sodiumcyanoborohydride (283 mg) and acetic acid (0.4 mL) were added to thereaction mixture, and the mixture was stirred for 1 hr. The reactionmixture was filtrated and the filtrate was evaporated under reducedpressure. Saturated aqueous sodium hydrogencarbonate solution was addedto the residue and the mixture was extracted with ethyl acetate. Theextract was dried and the solvent was evaporated under reduced pressure.The residue was purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(940 mg) as amorphous.

[0361] (2) The above-mentioned compound (940 mg) was dissolved in ethylacetate (3.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.8 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated solid was collected by filtration to give the titlecompound (655 mg).

[0362]¹H-NMR(DMSO-d₆)δ1.94-2.37(6H,m), 2.89-3.09(1H,m), 3.27-3.80(3H,m),3.90-4.10(1H,m), 4.23-4.44(2H,s), 4.53-4.69(1H,m), 4.80-5.20(1H,m),7.87(2H,d,J=8.4 Hz), 7.94(2H,d,J=8.4 Hz), 9.18(1H,brs), 10.60(2H,brs).

Example 32

[0363] Synthesis of(S)-1-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-2-cyanopyrrolidinedihydrochloride

[0364] (1)(S)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine[product of Example 31 (1), 1.04 g] and 37% formaldehyde solution (0.7mL) were dissolved in acetonitrile (15 mL), and the mixture was stirredat room temperature for 1 hr. Sodium cyanoborohydride (0.240 g) andacetic acid (0.4 mL) were added to the reaction mixture, and the mixturewas stirred for 1 hr. The reaction mixture was evaporated under reducedpressure. Saturated aqueous sodium hydrogencarbonate solution was addedto the residue and the mixture was extracted with chloroform. Theextract was dried and the solvent was evaporated under reduced pressure.The residue was purified by silica gel chromatography to give(S)-1-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-2-cyanopyrrolidine(0.71 g) as amorphous.

[0365] (2) The above-mentioned compound (0.70 g) was dissolved in ethylacetate (2.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.0 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated solid was collected by filtration to give the titlecompound (0.548 g).

[0366]¹H-NMR(DMSO-d₆)δ2.00-2.42(5H,m), 2.59(3H,s), 2.88-3.18(1H,m),3.50-5.20(9H,m), 7.89(2H,d,J=8.1 Hz), 7.97(2H,d,J=8.1 Hz), 9.26(1H,brs),10.96(1H,brs), 12.42(1H,brs).

Example 33

[0367] Synthesis of(S)-2-cyano-1-{(2S,4S)-4-[N,N-bis(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}pyrrolidinedihydrochloride

[0368] (1) The title compound (0.924 g) of Reference Example 3,4-cyanobenzyl bromide (1.27 g) and diisopropylethylamine (1.6 mL) weredissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture was stirredat room temperature for 15 hr. Water was added to the reaction mixtureand the mixture was extracted with ethyl acetate. The extract was driedand the solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give(S)-1-{(2S,4S)-1-tert-butoxycarbonyl-4-[N,N-bis(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-2-cyanopyrrolidine(1.11 g) as a white solid.

[0369] (2) The above-mentioned compound (0.95 g) was dissolved in ethylacetate (2.2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.2 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated solid was collected by filtration to give the titlecompound (0.85 g).

[0370]¹H-NMR(DMSO-d₆)δ1.72-2.37(5H,m), 2.62-2.79(1H,m), 3.06-3.43(2H,m),3.53-4.50(8H,m), 4.80-5.14(1H,m), 7.55(4H,d,J=8.1 Hz), 7.79(4H,d,J=8.1Hz), 8.90(1H,brs), 10.10(1H,brs).

Example 34

[0371] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(3-pyridylmethyl)amino-2-pyrrolidinylcarbonyl]pyrrolidine3 trifluoroacetate

[0372] (1) The title compound (928 mg) of Reference Example 3 andnicotinaldehyde (321 mg) were dissolved in methanol (16 mL), and themixture was stirred at room temperature for 30 min. Sodiumcyanoborohydride (189 mg) and several drops of acetic acid were added tothe reaction mixture, and the mixture was stirred at room temperaturefor 18 hr. The reaction mixture was filtrated and the filtrate wasevaporated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-pyridylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(591 mg).

[0373] (2) The above-mentioned compound (557 mg) was dissolved indichloromethane (14 mL) and trifluoroacetic acid (1.4 mL) was addedthereto. The mixture was stood at room temperature for 18 hr. Thereaction solvent was concentrated under reduced pressure, and diethylether was added to the residue. The precipitated solid was collected byfiltration to give the title compound (704 mg).

[0374]¹H-NMR(DMSO-d₆)δ1.70-2.40(5H,m), 2.91-3.14(1H,m), 3.29-3.73(5H,m),4.31(2H,s), 4.52-4.70(1H,m), 4.78-5.15(1H,m), 7.58(1H,dd,J=7.8,5.0 Hz),8.02(1H,d,J=7.9 Hz), 8.68(1H,dd,J=4.9, 1.4 Hz), 8.75(1H,d,J=1.7 Hz).

Example 35

[0375] Synthesis of(S)-2-cyano-1-((2S,4S)-4-phenethylamino-2-pyrrolidinylcarbonyl)pyrrolidine2 trifluoroacetate

[0376] (1) The title compound (462 mg) of Reference Example 3 andphenylacetaldehyde (0.18 mL) were dissolved in methanol (15 mL), and themixture was stirred at room temperature for 1 hr. Sodiumcyanoborohydride (94 mg) and acetic acid (0.1 mL) were added to thereaction mixture, and the mixture was stirred for 15 hr. The reactionmixture was filtrated and the filtrate was evaporated under reducedpressure. Saturated aqueous sodium hydrogencarbonate solution was addedto the residue and the mixture was extracted with ethyl acetate. Theextract was dried and the solvent was evaporated under reduced pressure.The residue was purified by silica gel chromatography to give(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-phenethylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(300 mg) as amorphous.

[0377] (2) The above-mentioned compound (300 mg) was dissolved indichloromethane (7.3 mL) and trifluoroacetic acid (0.73 ML) was addedthereto. The mixture was stood at room temperature for 15 hr. Thesolvent was evaporated under reduced pressure, and the residue waspurified by HPLC and freeze-dried to give the title compound (150 mg) asamorphous.

[0378]¹H-NMR(DMSO-d₆)δ1.85-2.38(5H,m), 2.83-3.08(3H,m), 3.15-3.74(4H,m),3.75-5.18(5H,m), 7.17-7.40(5H,m).

Example 36

[0379] Synthesis of(S)-2-cyano-1-((2S,4S)-4-cyclohexylamino-2-pyrrolidinylcarbonyl)pyrrolidinedihydrochloride

[0380] (1) The title compound (924 mg) of Reference Example 3 andcyclohexanone (0.34 mL) were dissolved in methanol (15 mL), and themixture was stirred at room temperature for 1 hr. Sodiumcyanoborohydride (200 mg) and acetic acid (0.4 mL) were added to thereaction mixture, and the mixture was stirred for 15 hr. The reactionmixture was evaporated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-(2S,4S)-1-tert-butoxycarbonyl-4-cyclohexylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(440 30 mg) as amorphous.

[0381] (2) The above-mentioned compound (430 mg) was dissolved in ethylacetate (1.5 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.4 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated solid was collected by filtration to give the titlecompound (338 mg).

[0382]¹H-NMR(DMSO-d₆)δ1.01-1.47(5H,m), 1.54-2.38(10H,m),2.88-3.07(2H,m), 3.38-3.70(4H,m), 3.95-4.13(1H,m), 4.40-4.61(1H,m),4.80-5.14(1H,m), 9.68(1H,brs), 9.89(1H,brs).

Example 37

[0383] Synthesis of(S)-2-cyano-1-((2S,4S)-4-diethylamino-2-pyrrolidinylcarbonyl)pyrrolidinedihydrochloride

[0384] (1) The title compound (924 mg) of Reference Example 3 and 90%aqueous acetaldehyde solution (1.7 mL) were dissolved in methanol (15mL), and the mixture was stirred at room temperature for 3 hr. Sodiumcyanoborohydride (440 mg) and acetic acid (0.4 mL) were added to thereaction mixture, and the mixture was stirred for 1 hr. The reactionmixture was evaporated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-diethylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(720 mg) as amorphous.

[0385] (2) The above-mentioned compound (720 mg) was dissolved in ethylacetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.5 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr. Theprecipitated solid was collected by filtration to give the titlecompound (713 mg.).

[0386]¹H-NMR(DMSO-d₆)δ1.20-1.30(6H,m), 1.94-2.36(1H,m), 2.87-3.38(6H,m),3.52-4.18(8H,m), 4.45-4.64(1H,m), 4.82-4.90(1H,m), 9.38(1H,brs),11.30(1H,brs), 11.82(1H,brs).

Example 38

[0387] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(1-piperidino)-2-pyrrolidinylcarbonyl]pyrrolidinedihydrochloride

[0388] (1) The title compound (924 mg) of Reference Example 3 and 50%aqueous glutaraldehyde solution (0.8 mL) were dissolved in methanol (15mL), and the mixture was stirred at room temperature for 3 hr. Sodiumcyanoborohydride (630 mg) and acetic acid (0.4 mL) were added thereaction mixture-and the mixture was stirred for 1 hr. The reactionmixture was evaporated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-piperidino)-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(480 mg) as amorphous.

[0389] (2) The above-mentioned compound (470 mg) was dissolved in ethylacetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.6 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr. Theprecipitated solid was collected by filtration to give the titlecompound (485 mg).

[0390]¹H-NMR(DMSO-d₆)δ1.30-1.50(1H,m), 1.61-1.90(5H,m), 1.99-2.32(3H,m),2.83-3.09(2H,m), 3.31-3.80(8H,m), 3.90-4.07(1H,m), 4.40-4.62(1H,m),4,80-5.20(1H,m), 9.27(1H,brs), 11.10(1H,brs), 11.64(1H,brs).

Example 39

[0391] Synthesis of(S)-2-cyano-1-{(2S,4S)-4-[N,N-bis(ethoxycarbonylmethyl)amino]-2-pyrrolidinylcarbonyl}pyrrolidinedihydrochloride

[0392] (1) The title compound (0.924 g) of Reference Example 3, ethylbromoacetate (0.73 mL) and diisopropylethylamine (1.6 mL) were dissolvedin N-methyl-2-pyrrolidone (10 mL), and the mixture was stirred at roomtemperature for 15 hr. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was dried and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give(S)-1-{(2S,4S)-1-tert-butoxycarbonyl-4-[N,N-bis(ethoxycarbonylmethyl)amino]-2-pyrrolidinylcarbonyl}-2-cyanopyrrolidine(0.95 g) as a white solid.

[0393] (2) The above-mentioned compound (0.80 g) was dissolved in ethylacetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2 mL) wasadded thereto. The mixture was stood at room temperature for 15 hr. Theprecipitated solid was collected by filtration to give the titlecompound (0.65 g).

[0394]¹H-NMR(DMSO-d₆)δ1.19(6H,t,J=7.2 Hz), 1.57-1.74(1H,m),1.93-2.34(4H,m), 2.96-3.42(2H,m), 3.75-4.50(12H,m), 4.78-5.12(1H,m),8.80(1H,brs), 10.19(1H,brs).

Example 40

[0395] Synthesis of(S)-1-((2S,4S)-4-benzoylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidinehydrochloride

[0396] (1)(2S,4S)-4-Benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid (title compound of Reference Example 7, 1.1 g) and(S)-2-cyanopyrrolidine hydrochloride (0.44 g) were dissolved in DMF (10mL), and triethylamine (0.98 mL), HOBT (0.54 g) and EDC hydrochloride(0.67 g) were successively added. The mixture was stirred at roomtemperature for 15 hr. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was dried andevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-((2S,4R)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(1.0 g) as a white solid.

[0397] (2) The above-mentioned compound (0.91 g) was dissolved intetrahydrofuran (3 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (6 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated white solid was collected by filtration to give thetitle compound (541 mg).

[0398]¹H-NMR(DMSO-d₆)δ1.63-2.36(5H,m), 2.75-2.93((1H,m),3.21-3.80(4H,m), 4.51-5.13(3H,m), 7.40-7.90(2H,m), 8.52-9.00(2H,m),10.06(1H,brs).

Example 41

[0399] Synthesis of(S)-1-((2S,4R)-4-benzoylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidinehydrochloride

[0400] (1)(2S,4R)-4-Benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylicacid (title compound of Reference Example 8, 1.6 g) and(S)-2-cyanopyrrolidine hydrochloride (0.63 g) were dissolved in DMF (10mL), and triethylamine (1.32 mL), HOBT (0.79 g) and EDC hydrochloride(0.99 g) were successively added. The mixture was stirred at roomtemperature for 15 hr. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was dried andevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-((2S,4R)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(1.2 g) as a white solid.

[0401] (2) The above-mentioned compound (0.97 g) was dissolved in 4mol/L hydrochloric acid-1,4-dioxane (6 mL). The mixture was stood atroom temperature for 15 hr. The precipitated white solid was collectedby filtration to give the title compound (0.814 g).

[0402]¹H-NMR(DMSO-d₆)δ1.96-2.65(6H,m), 3.23-3.71(4H,m), 4.42-5.15(3H,m),7.51-7.97(5H,m), 8.67-9.03(2H,m), 9.92(1H,brs).

Example 42

[0403] Synthesis of(S)-1-[(2S,4S)-4-(4-chlorobenzoyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinehydrochloride

[0404] (1) The title compound (462 mg) of Reference Example 3 andtriethylamine (0.42 mL) were dissolved in dichloromethane (30 mL), and4-chlorobenzoyl chloride (0.19 mL) was added under ice-cooling. Themixture was stirred at room temperature for 24 hr. Water was added tothe reaction mixture and the mixture was extracted with dichloromethane.The extract was dried and evaporated under reduced pressure. The residuewas purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-chlorobenzoyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(617 mg) as amorphous.

[0405] (2) The above-mentioned compound (610 mg) was dissolved intetrahydrofuran (4 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (3.4mL) was added thereto. The mixture was stirred at room temperature for24 hr. The solvent was evaporated under reduced pressure, and theconcentrate was purified by HPLC and freeze-dried to give the titlecompound (340 mg) as amorphous.

[0406]¹H-NMR(DMSO-d₆)δ1.87-2.34(5H,m), 2.78-2.93(1H,m), 3.20-3.75(4H,m),4.54-4.72(2H,m), 4.85(1H,dd,J=7.8,4.7 Hz), 7.58(2H,d,J=8.5 Hz),7.86(2H,d,J=8.5 Hz), 8.70(1H,d,J=6.8 Hz), 8.88(1H,brs), 9.74(1H,brs).

Example 43

[0407] Synthesis of(S)-2-cyano-1-[(2S,4s)-4-(4-trifluoromethylbenzoyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0408] (1) The title compound (462 mg) of Reference Example 3,4-trifluoromethylbenzoic acid (285 mg) and triethylamine (0.42 mL) weredissolved in DMF (30 mL), and HOBT (241 mg) and EDC hydrochloride (302mg) were successively added under ice-cooling. The mixture was stirredat room temperature for 22 hr. The solvent was evaporated under reducedpressure, and saturated aqueous sodium hydrogencarbonate solution wasadded to the concentrate. The mixture was extracted with ethyl acetate.The extract was washed with brine, dried and evaporated under reducedpressure. The residue was purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-trifluoromethylbenzoyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(640 mg) as a colorless oil.

[0409] (2) The above-mentioned compound (640 mg) was dissolved intetrahydrofuran (15 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (3.3mL) was added thereto. The mixture was stirred at room temperature for24 hr. The solvent was evaporated under reduced pressure and theconcentrate was purified by HPLC and freeze-dried to give the titlecompound (163 mg) as amorphous.

[0410]¹H-NMR(DMSO-d₆)δ1.92-2.37(5H,m), 2.82-2.96(1H,m), 3.24-3.65(4H,m),4.67-4.76(2H,m), 4.89(1H,dd,J=7.8,4.7),7.90(2H,d,J=8.2 Hz),8.06(2R,d,J=8.2 Hz), 8.90(1H,d,J-6.7 Hz), 9.0-10.0(2H,m).

Example 44

[0411] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-cyanobenzoyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinehydrochloride

[0412] (1) The title compound (462 mg) of Reference Example 3,4-cyanobenzoic acid (221 mg) and triethylamine (0.42 mL) were dissolvedin DMF (30 mL), HOBT (241 mg) and EDC hydrochloride (302 mg) weresuccessively added under ice-cooling. The mixture was stirred at roomtemperature for 21 hr. The solvent was evaporated under reducedpressure, and saturated aqueous sodium hydrogencarbonate solution wasadded to the concentrate. The mixture was extracted with ethyl acetate.The extract was washed with brine, dried and evaporated under reducedpressure. The residue was purified by silica gel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanobenzoyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(548 mg) as amorphous.

[0413] (2) The above-mentioned compound (548 mg) was dissolved intetrahydrofuran (15 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (3.1mL) was added thereto. The mixture was stirred at room temperature for 5days. The solvent was evaporated under reduced pressure, and theconcentrate was purified by HPLC and freeze-dried to give the titlecompound (177 mg) as amorphous.

[0414]¹H-NMR(DMSO-d₆)δ1.93-2.36(5H,m), 2.80-2.96(1H,m), 3.26-3.68(4H,m),4.58-4.76(2H,m), 4.88(1H,dd,J=7.7,4.8 Hz), 8.00(4H,s), 8.93(1H,d,J=6.6Hz), 9.0-10.0(2H,m).

Example 45

[0415] Synthesis of(S)-2-cyano-1-((2S,4S)-4-nicotinoylamino-2-pyrrolidinylcarbonyl)pyrrolidine2 trifluoroacetate

[0416] (1) The title compound (462 mg) of Reference Example 3 andtriethylamine (0.63 mL) were dissolved in tetrahydrofuran (10 mL), andnicotinoyl chloride hydrochloride (285 mg) was added thereto. Themixture was stirred at room temperature for 15 hr. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The extract was dried and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography to give(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-nicotinoylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(190 mg) as amorphous.

[0417] (2) The above-mentioned compound (180 mg) was dissolved indichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was addedthereto. The mixture was stood at room temperature for 15 hr. Thesolvent was evaporated under reduced pressure, and the residue waspurified by HPLC and freeze-dried to give the title compound (96 mg) asamorphous.

[0418]¹H-NMR(DMSO-d₆)δ1.86-2.36(5H,m), 2.80-2.97(1H,m), 3.24-3.68(4H,m),4.49-5.13(3H,m), 7.58(1H,dd,J=7.8,4.8 Hz), 8.24(1H,d,J=7.8 Hz),8.76(1H,d,J=4.8 Hz), 8.87(1H,d,J=6.6 Hz), 9.03(1H,s), 9.93(1H,brs).

Example 46

[0419] Synthesis of(S)-2-cyano-1-((2S,4S)-4-isonicotinoylamino-2-pyrrolidinylcarbonyl)pyrrolidine2 trifluoroacetate

[0420] (1) The title compound (462 mg) of Reference Example 3 andtriethylamine (0.63 mL) were dissolved in tetrahydrofuran (10 mL), andisonicotinoyl chloride hydrochloride (285 mg) was added thereto. Themixture was stirred at room temperature for 15 hr. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The extract was dried and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography to give(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-isonicotinoylamino-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (670 mg)as amorphous.

[0421] (2) The above-mentioned compound (650 mg) was dissolved indichloromethane (16 mL) and trifluoroacetic acid (1.6 mL) was addedthereto. The mixture was stood at room temperature for 15 hr. Thesolvent was evaporated under reduced pressure, and the residue waspurified by HPLC and freeze-dried to give the title compound (412 mg) asamorphous.

[0422]¹H-NMR(DMSO-d₆)δ1.87-2.36(5H,m), 2.79-2.96(1H,m), 3.20-3.68(4H,m),4.48-5.15(3H,m), 7.80(2H,d,J=6.0 Hz), 8.70-9.13(4H,m), 9.93(1H,brs).

Example 47

[0423] Synthesis of(S)-2-cyano-1-((2S,4S)-4-glycylamino-2-pyrrolidinylcarbonyl)pyrrolidinedihydrochloride

[0424] (1) The title compound (464 mg) of Reference Example 3 andN-methylmorpholine (0.16 mL) were dissolved in tetrahydrofuran (10 mL),and isobutyl chloroformate (0.19 mL) was added thereto at −20° C. Themixture was stirred for 30 min, and a solution ofN-tert-butoxycarbonylglycine (463 mg) and triethylamine (0.21 mL) in DMF(3 mL) was added thereto at −20° C. The mixture was stirred at roomtemperature for 20 hr. Saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The extract was washed with brine, dried andevaporated under reduced pressure. The residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(N-tert-butoxycarbonylglycyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(680 mg) as amorphous.

[0425] (2) The above-mentioned compound (360 mg) was dissolved in1,4-dioxane (1 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (4 mL) wasadded thereto. The mixture was stirred at room temperature for 4 hr. Theprecipitated solid was collected by filtration to give the titlecompound (262 mg) as a white solid.

[0426]¹H-NMR(DMSO-d₆)δ1.7-2.3(5H,m), 2.78(1H,m), 3.5(2H,m),4.26-4.60(2H,m), 4.84(1H,dd,J=7.9,4.6 Hz), 8.24(3H,brs), 8.7-9.1(2H,m),10.71(1H,brs).

Example 48

[0427] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(ethoxyoxalyl)amino-2-pyrrolidinylcarbonyl]pyrrolidinetrifluoroacetate

[0428] (1) The title compound (464 mg) of Reference Example 3 andtriethylamine (0.63 mL) were dissolved in tetrahydrofuran (10 mL), andethyl chloroglyoxylate (0.18 mL) was added thereto under ice-cooling.The mixture was stirred for 2 hr and the solvent was evaporated underreduced pressure. Saturated aqueous sodium hydrogencarbonate solutionwas added to the concentrate and the mixture was extracted with ethylacetate. The extract was washed with brine and dried. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel chromatography to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(ethoxyoxalyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(615 mg) as amorphous.

[0429] (2) The above-mentioned compound (492 mg) was dissolved inacetonitrile (10 mL), and trifluoroacetic acid (2 mL) was added theretounder ice-cooling. The mixture was stood at room temperature for 28 hr.The solvent was evaporated under reduced pressure, and the residue waspurified by HPLC and freeze-dried to give the title compound (168 mg) asamorphous.

[0430]¹H-NMR(DMSO-d₆)δ1.27(3H,t,J=7.1 Hz), 1.82-2.35(5H,m), 2.82(1H,m),3.26(1H,dd,J=11.5,7.1 Hz), 3.45(1H,dd,J=11.5,7.1 Hz), 3.5(2H,m),4.24(2H,q,J=7.1 Hz), 4.43-4.62(2H,m), 4.85(1H,dd,J=7.8,4.8 Hz),8.89(1H,brs), 9.18(1H,d,J=7.8 Hz), 9.78(1H,brs).

Example 49

[0431] Synthesis of(S)-2-cyano-1-[(2S,4S)-4-(4-pyridyl)oxy-2-pyrrolidinylcarbonyl]pyrrolidinedihydrochloride

[0432] (1) The title compound (464 mg) of Reference Example 2,4-hydroxypyridine (144 mg) and triphenylphosphine (393 mg) weredissolved in tetrahydrofuran (20 mL), and 40% toluene solution (0.71 mL)of diethyl diazodicarboxylate was added thereto. The mixture was stirredfor 9 days. The solvent was evaporated under reduced pressure, and theconcentrate was purified by HPLC and freeze-dried to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-pyridyl)oxy-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(178 mg) as amorphous.

[0433] (2) The above-mentioned compound (173 mg) was dissolved in ethylacetate (1.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.6 mL)was added thereto. The mixture was stood at room temperature for 5 hr.The precipitated white solid was collected by filtration to give thetitle compound (159 mg).

[0434]¹H-NMR(DMSO-d₆)δ1.73-2.42(5H,m), 2.87-3.03(1H,m), 3.2-3.8(4H,m),4.66-4.87(2H,m), 5.53-5.67(m,1H),7.52(1H,d,J=7.2 Hz), 8.78(1H,d,J=7.2Hz), 8.81(1H,d,J=7.2 Hz), 8.96(1H,brs), 10.86(1H,brs).

Example 50

[0435] Synthesis of(S)-1-[(2S,4S)-4-(4-aminobenzoyl)oxy-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidinedihydrochloride

[0436] (1) The title compound (619 mg) of Reference Example 1 andtriethylamine (0.84 mL) were dissolved in dichloromethane (10 mL), and4-nitrobenzoyl chloride (557 mg) and 4-dimethylaminopyridine (24 mg)were added thereto. The mixture was stirred at room temperature for 14hr. Saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture and the mixture was extracted with chloroform. Theextract was washed with brine and dried. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelchromatography and recrystallized from ethyl acetate-hexane to give(S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrobenzoyl)oxy-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(800 mg) as pale-brown crystals.

[0437] (2) The above-mentioned compound (600 mg) was dissolved in ethylacetate (15 mL), and the mixture was stirred under a hydrogenatomosphere (1 atm) in the presence of 10% palladium/carbon (123 mg) for3 hr. The reaction mixture was filtrated and the filtrate wasconcentrated under reduced pressure. The residue was crystallized fromethyl acetate-hexane to give(S)-1-[(2S,4S)-4-(4-aminobenzoyl)oxy-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine(96 mg) as white crystals.

[0438] (3) The above-mentioned compound (518 mg) was dissolved in ethylacetate (1.2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.5 mL)was added thereto. The mixture was stood at room temperature for 15 hr.The precipitated pale-brown solid was collected by filtration to givethe title compound (378 mg).

[0439]¹H-NMR(DMSO-d₆)δ1.97-2.38(5H,m), 2.76-2.88(1H,m), 3.40-3.70(4H,m),4.63-4.76(1H,m), 4.88(1H,dd,J=7.9,5.3 Hz),5.42-5.50(m,1H),6.71(1H,d,J=8.7 Hz), 7.72(1H,d,J=8.7 Hz), 8.88(1H,brs),10.84(1H,brs).

Example 51

[0440] Synthesis of(S)-2-cyano-1-((2S,4S)-4-nicotinoyloxy-2-pyrrolidinylcarbonyl)pyrrolidinedihydrochloride

[0441] (1) The title compound (619 mg) of Reference Example 1 andtriethylamine (0.84 mL) were dissolved in dichloromethane (10 mL), andnicotinoyl chloride hydrochloride (534 mg) and 4-dimethylaminopyridine(23 mg) were added thereto. The mixture was stirred at room temperaturefor 15 hr. Saturated aqueous sodium hydrogencarbonate solution was addedto the reaction mixture and the mixture was extracted with chloroform.The extract was washed with brine and dried. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gelchromatography and recrystallized from ethyl acetate-hexane to give(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-nicotinoyloxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(731 mg) as pale-yellow crystals.

[0442] (2) The above-mentioned compound (414 mg) was dissolved in ethylacetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.25 mL) wasadded thereto. The mixture was stood at room temperature for 18 hr. Theprecipitated white solid was collected by filtration to give the titlecompound (524 mg).

[0443]¹H-NMR(DMSO-d₆)δ1.97-2.45(5H,m), 2.81-2.96(1H,m), 3.45-3.85(4H,m),4.67-4.78(1H,m), 4.86(1H,dd,J=7.9,5.0 Hz),5.60-5.67(m,1H),7.65(1H,dd,J=8.0,5.1 Hz), 8.40-8.47(1H,m),8.88(1H,dd,J=5.0,1.6 Hz), 9.02(1H,brs), 9.17(1H,d,J=1.8 Hz),10.94(1H,brs).

Example 52

[0444] Synthesis of(S)-2-cyano-1-((2S,4S)-4-isonicotinoyloxy-2-pyrrolidinylcarbonyl)pyrrolidinedihydrochloride

[0445] (1) The title compound (752 mg) of Reference Example 1 andtriethylamine (0.84 mL) were dissolved in dichloromethane (10 mL), andisonicotinoyl chloride hydrochloride (712 mg) and4-dimethylaminopyridine (40 mg) were added thereto. The mixture wasstirred at room temperature for 22 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with chloroform. The extract was washed with brineand dried. The solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography and crystallized fromdiethyl ether to give(S)-1-((2S,4S)-1-tert-butoxycarbonyl-4-isonicotinoyloxy-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine(576 mg) as white crystals.

[0446] (2) The above-mentioned compound (414 mg) was dissolved in ethylacetate (1.0 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.25 mL)was added thereto. The mixture was stood at room temperature for 18 hr.The precipitated white solid was collected by filtration to give thetitle compound (458 mg).

[0447]¹H-NMR(DMSO-d₆)δ1.97-2.47(5H,m), 2.79-2.92(1H,m), 3.5-3.8(4H,m),4.68-4.81(1H,m), 4.87(1H,dd,J=7.9,5.3 Hz),5.60-5.67(m,1H),7.97(2H,d,J=6.0 Hz), 8.83(2H,d,J=6.0 Hz), 8.97(1H,brs),10.98(1H,brs).

Example 53

[0448] Synthesis of3-((2S,4S)-4-amino-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[0449]3-((2S,4S)-4-Amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(title compound of Reference Example 10, 400 mg) was dissolved in ethylacetate (3.0 mL), and 4 mol/L hydrochloric acid-ethyl acetate (3.75 mL)was added thereto. The mixture was stood at room temperature for 3 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was dissolved in ethanol (100 mL).

[0450] Activated carbon (0.4 g) was added thereto and the activatedcarbon was filtered off. The filtrate was concentrated and diethyl etherwas added thereto. The precipitated solid was collected by filtration togive the title compound (28.8 mg) as a white powder.

[0451]¹H-NMR(DMSO-d₆)δ1.85-2.06(1H,m), 2.71-2.93(1H,m), 2.99-3.20(2H,m),3.40-3.98(5H,m), 4.37-4.78(3H,m), 8.86(5H,brs).

Example 54

[0452] Synthesis of3-[(2S,4S)-4-(4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0453] (1) The title compound (1810 mg) of Reference Example 10,diisopropylethylamine (3.14 mL) and 4-fluorobenzonitrile (727 mg) weredissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture was stirredat 100° C. for 24 hr. The reaction mixture was poured into saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(170 mg) as a pale-brown oil.

[0454] (2) The above-mentioned compound (170 mg) was dissolved in ethylacetate (0.42 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.53 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration to give the titlecompound (69.3 mg) as a pale-brown powder.

[0455]¹H-NMR(DMSO-d₆)δ1.64-1.80(1H,m), 2.84-3.20(4H,m), 3.45-3.96(3H,m),4.15-4.34(1H,m), 4.39-4.78(3H,m), 6.70(2H,d,J=8.8 Hz), 6.85-7.01(1H,m),7.52(1H,d,J=8.7 Hz), 9.45(2H,brs).

Example 55

[0456] Synthesis of3-[(2S,4S)-4-(4-nitrophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0457] (1) The title compound (904 mg) of Reference Example 10,diisopropylethylamine (1.57 mL) and 4-fluoronitrobenzene (423 mg) weredissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture was stirredat 80° C. for 24 hr. The reaction mixture was poured into saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(919 mg) as yellow amorphous.

[0458] (2) The above-mentioned compound (795 mg) was dissolved in ethylacetate (3.8 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.4 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration to give the titlecompound (647 mg) as a yellow powder.

[0459]¹H-NMR(DMSO-d₆)δ1.68-1.87(1H,m), 2.88-3.30(4H,m), 3.48-3.98(3H,m),4.24-4.80(4H,m), 6.72(2H,d,J=9.3 Hz), 7.40-7.56(1H,m), 8.04(2H,d,J=7.5Hz), 9.51(2H,brs).

Example 56

[0460] Synthesis of3-[(2S,4S)-4-(4-methanesulfonylphenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0461] (1) The title compound (904 mg) of Reference Example 10,diisopropylethylamine (1.57 mL) and 4-fluorophenyl methyl sulfone (523mg) were dissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture wasstirred at 100° C. for 18 hr. The reaction mixture was poured intosaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-methanesulfonylphenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(27 mg).

[0462] (2) The above-mentioned compound (27 mg) was dissolved in ethylacetate (0.2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.1 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration to give the titlecompound (19.4 mg).

[0463]¹H-NMR(DMSO-d₆)δ1.65-1.82(1H,m), 2.89-3.23(7H,m), 3.49-3.98(3H,m),4.18-4.78(4H,m), 6.74(2H,d,J=9.0 Hz), 6.80-6.92(1H,m), 6.63(2H,d,J=9.0Hz), 9.30(2H,brs).

Example 57

[0464] Synthesis of3-[(2S,4S)-4-(2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0465] (1) The title compound (1810 mg) of Reference Example 10,diisopropylethylamine (3.14 mL) and 2-fluorobenzonitrile (727 mg) weredissolved in N-methyl-2-pyrrolidone (18 mL), and the mixture was stirredat 80° C. for 32 hr. The reaction mixture was poured into saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(88 mg).

[0466] (2) The above-mentioned compound (88 mg) was dissolved in ethylacetate (0.4 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.3 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration to give the titlecompound (25 mg).

[0467]¹H-NMR(DMSO-d₆)δ1.74-1.95(1H,m), 2.85-3.16(3H,m), 3.30-3.92(4H,m),4.27-4.79(4H,m), 6.15-6.27(1H,m), 6.77(1H,t,J=7.5 Hz), 6.87(1H,d,J=8.4Hz), 7.38-7.59(2H,m), 8.90(1H,brs), 10.80(1H,brs).

Example 58

[0468] Synthesis of3-[(2S,4S)-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0469] (1) The title compound (904 mg) of Reference Example 10,diisopropylethylamine (1.57 mL) and 2-chloro-5-cyanopyridine (416 mg)were dissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture wasstirred at 80° C. for 18 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(807 mg) as white amorphous.

[0470] (2) The above-mentioned compound (711 mg) was dissolved in ethylacetate (1.76 mL) and 4 mol/L hydrochloric acid-ethyl-acetate (2.20 mL)was added thereto. The mixture was stood at room temperature for 18 hr.The precipitated solid was collected by filtration to give the titlecompound (709 mg) as a white powder.

[0471]¹H-NMR(DMSO-d₆)δ1.74-1.94(1H,m), 2.78-2.94(1H,m), 2.97-3.26(3H,m),3.40-3.77(3H,m), 4.40-4.80(4H,m), 6.64(1H,d,J=9.0 Hz),7.77(1H,dd,J=8.7,2.4 Hz), 8.08(1H,brs), 8.46(1H,d,J=1.8 Hz),8.86(1H,brs), 10.37(1H,brs).

Example 59

[0472] Synthesis of 3-[(2S,4S)-4-(3,4-dicyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0473] (1) The title compound (0.904 g) of Reference Example 10,diisopropylethylamine (1.57 mL) and 4-fluorophthalonitrile (0.438 g)were dissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture wasstirred at 80° C. for 4 hr. The reaction mixture was poured intosaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3,4-dicyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1.08 g) as white amorphous.

[0474] (2) The above-mentioned compound (0.924 g) was dissolved in ethylacetate (2.16 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.70 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration to give the titlecompound (0.782 g) as a yellow powder.

[0475]¹H-NMR(DMSO-d₆)δ1.66-1.84(1H,m), 2.90-3.27(4H,m), 3.49-3.95(3H,m),4.20-4.40(1H,m), 4.40-5.79(3H,m), 7.00(1H,dd,J=8.7,2.4 Hz), 7.22(1H,s),7.52-7.67(1H,m), 7.76(1H,d,J=9.0 Hz).

Example 60

[0476] Synthesis of3-[(2S,4S)-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-I,3-thiazolidinehydrochloride

[0477] (1) The title compound (0.904 g) of Reference Example 10,diisopropylethylamine (1.57 mL) and 2-chloro-4-fluorobenzonitrile (0.467g) were dissolved in N-methyl-2-pyrrolidone 9 mL), and the mixture wasstirred at 80° C. for 8 hr. The reaction mixture was poured intosaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(0.630 g) as a colorless transparent oil.

[0478] (2) The above-mentioned compound (0.630 g) was dissolved in ethylacetate (2.88 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.80 mL)was added thereto. The mixture was stirred at room temperature for 18hr, and the precipitated solid was collected by filtration to give thetitle compound (0.465 g) as a white powder.

[0479]¹H-NMR(DMSO-d₆)δ1.65-1.81(1H,m), 2.84-2.99(1H,m), 2.99-3.22(3H,m),3.48-3.95(3H,m), 4.16-4.37(1H,m), 4.39-4.78(3H,m), 6.68(1H,dd,J=8.7,2.1Hz), 6.85(1H,d,J=1.8 Hz), 7.30-7.45(1H,m), 7.60(1H,d,J=8.7 Hz),9.60(2H,brs).

Example 61

[0480] Synthesis of3-[(2S,4S)-4-(2-benzoxazolyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0481] (1) The title compound (904 mg) of Reference Example 10,diisopropylethylamine (1.57 mL) and 2-chlorobenzoxazole (461 mg) weredissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture was stirredat room temperature for 1 hr. The reaction mixture was poured intosaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-[(2S,4S)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(975 mg) as white amorphous.

[0482] (2) The above-mentioned compound (862 mg) was dissolved in ethylacetate (4.1 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.6 mL)was added thereto. The mixture was stirred at room temperature for 8 hr.The precipitated solid was collected by filtration to give the titlecompound (656 mg) as a white powder.

[0483]¹H-NMR(DMSO-d₆)δ1.94-2.13(1H,m), 2.85-2.99(1H,m), 3.00-3.20(2H,m),3.31-4.00(4H,m), 4.40-4.82(4H,m), 7.07(1H,td,J=7.8,1.2 Hz),7.18(1H,td,J=7.8,1.2 Hz), 7.33(1H,d,J=7.2 Hz), 7.42(1H,d,J=7.5 Hz),8.61(1H,brs), 8.89(1Hbrs), 10.59(1H,brs).

Example 62

[0484] Synthesis of3-((2S,4S)-4-benzylamino-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[0485] (1) The title compound (904 mg) of Reference Example 10 andbenzaldehyde (318 mg) were dissolved in methanol (16 mL), and themixture was stirred at room temperature for 30 min. Sodiumcyanoborohydride (189 mg) and several drops of acetic acid were added tothe reaction mixture, and the mixture was stirred for 6 hr. The reactionmixture was evaporated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-[(2S,4S)-4-benzylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(742 mg) as a colorless transparent oil.

[0486] (2) The above-mentioned compound (742 mg) was dissolved in ethylacetate (3.8 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.4 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the precipitated solid was collected by filtration to give the titlecompound (540 mg) as a white powder.

[0487]¹H-NMR(DMSO-d₆)δ2.10-2.32(1H,m), 2.86-3.20(3H,m), 3.49-4.03(5H,m),4.21(2H,s), 4.39-4.80(3H,m), 7.31-7.52(3H,m), 7.52-7.72(2H,m),10.17(4H,brs).

Example 63

[0488] Synthesis of3-[(2S,4S)-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0489] (1) The title compound (904 mg) of Reference Example 10 and4-cyanobenzaldehyde (393 mg) were dissolved in methanol (16 mL), and themixture was stirred at room temperature for 30 min. Sodiumcyanoborohydride (189 mg) and several drops of acetic acid were added tothe reaction mixture, and the mixture was stirred for 18 hr. Thereaction mixture was evaporated under reduced pressure. Saturatedaqueous sodium hydrogencarbonate solution was added to the residue andthe mixture was extracted with ethyl acetate. The extract was dried andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(389 mg) as a colorless transparent oil.

[0490] (2) The above-mentioned compound (389 mg) was dissolved in ethylacetate (0.9 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.2 mL)was added thereto. The mixture was stood at room temperature for 18 hr.The precipitated solid was collected by filtration to give the titlecompound (286 mg) as a white powder.

[0491]¹H-NMR(DMSO-d₆)δ2.06-2.34(1H,m), 2.85-3.01(1H,m), 3.01-3.20(2H,m),3.50-4.06(5H,m), 4.30(2H,s), 4.41-4.79(3H,m), 7.80(2H,d,J=8.1 Hz),7.95(2H,d,J=8.4 Hz), 9.05(1H,brs), 10.30(3H,brs).

Example 64

[0492] Synthesis of3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0493] (1)3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine[product of Example 63 (1), 1.35 g] and 37% formaldehyde solution (0.788mL) were dissolved in acetonitrile (20 mL), and the mixture was stirredat room temperature for 30 min. Sodium cyanoborohydride (0.305 g) andseveral drops of acetic acid were added to the reaction mixture, and thereaction mixture was stirred for 1 hr. The reaction mixture wasevaporated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.953 g) as white amorphous.

[0494] (2) The above-mentioned compound (0.818 g) was dissolved in ethylacetate (3.8 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.4 mL)was added thereto. The mixture was stirred at room temperature for 5 hr.The precipitated solid was collected by filtration to give the titlecompound (0.683 g) as a white powder.

[0495]¹H-NMR(DMSO-d₆)δ2.20-2.48(1H,m), 2.57(3H,s), 2.80-3.20(3H,m),3.57-4.17(5H,m), 4.20-4.85(5H,m), 7.88(2H,d,J=7.8 Hz), 7.96(2H,d,J=8.4Hz), 9.12(1H,brs), 10.95(1H,brs), 12.50(1H,brs).

Example 65

[0496] Synthesis of3-[(2S,4R)-4-(7-methoxy-2-phenyl-4-quinolyl)oxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrihydrochloride

[0497] (1) N-tert-Butoxycarbonyl-L-trans-hydroxyproline (5.67 g) wasdissolved in dimethyl sulfoxide (70 mL), and potassium tert-butoxide(6.88 g) was gradually added thereto at room temperature. The mixturewas stirred for 1.5 hr. 4-Chloro-7-methoxy-2-phenylquinoline (7.28 g)was gradually added to this solution, and the mixture was stirred for 17hr. Water was added to the reaction mixture and the mixture was washedwith ethyl acetate/hexane (1/1). The aqueous layer was adjusted to pH 4with 1 mol/L hydrochloric acid, and the precipitate was collected byfiltration to give(2S,4R)-1-tert-butoxycarbonyl-4-(7-methoxy-2-phenyl-4-quinolyl)oxy-2-pyrrolidine-2-carboxylicacid (8.00 g) as a white solid.

[0498] (2) Using the above-mentioned compound (546 mg) and in the samemanner as in Reference Example 9,3-[(2S,4R)-1-tert-butoxycarbonyl-4-(7-methoxy-2-phenyl-4-quinolyl)oxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(568 mg) was obtained as a white solid.

[0499] (3) Using the above-mentioned compound (554 mg) and in the samemanner as in Example 5 (2), the title compound (521 mg) was obtained asa white powder.

[0500]¹H-NMR(500 MHz,DMSO-d₆)δ2.40-2.50(1H,m), 2.96-3.12(3H,m),3.68-3.97(4H,m), 3.99(3H,s), 4.48-4.94(3H,m), 4.98(1H,brs),7.43(1H,d,J=8.1 Hz), 7.69-7.70(4H,m), 7.91(1H,brs), 8.26(2H,d,J=7.4 Hz),8.57(1H,brs), 9.10(1H,brs), 11.00(1H,brs).

Example 66

[0501] Synthesis of3-((2S,4S)-4-benzoyloxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine

[0502] (1) Using the title compound (643 mg) of Reference Example 11 andbenzoyl chloride (0.44 mL), and in the same manner as in Example 50 (1),3-((2S,4S)-4-benzoyloxy-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(515 mg) was obtained as an oil.

[0503] (2) The above-mentioned compound (413 mg) was dissolved in ethylacetate (4 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.3 mL) wasadded thereto. The mixture was stirred at room temperature for 14 hr andthe solvent was evaporated under reduced pressure. The residue was addedto aqueous sodium hydrogencarbonate solution and extracted with ethylacetate. The extract was washed with brine and dried. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel chromatography to give the title compound (315 mg) as an oil.

[0504]¹H-NMR(DMSO-d₆)δ1.83-1.93(1H,m), 2.45-2.57(1H,m),2.87(1H,dd,J=12.8,4.2 Hz), 2.99(1H,t,J=6.3 Hz), 3.08(1H,t,J=6.3 Hz),3.19(1H,d,J=12.8 Hz), 3.57-3.77(1.5H,m), 3.83-3.98(1.5H,m),4.42(0.5H,d,J=9.5 Hz), 4.48-4.58(1H,m), 4.72(0.5H,d,J=9.5 Hz),5.28-5.36(1H,m), 7.52(2H,t,J=7.4 Hz), 7.65(1H,t,J=7.4 Hz),7.93(2H,d,J=7.4 Hz).

Example 67

[0505] Synthesis of3-[(2S,4S)-4-(4-cyanobenzoyl)oxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine

[0506] (1) Using the title compound (445 mg) of Reference Example 11 and4-cyanobenzoyl chloride (371 mg), and in the same manner as in Example50 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanobenzoyl)oxy-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(519 mg) was obtained as a pale-brown solid.

[0507] (2) Using the above-mentioned compound (386 mg), and in the samemanner as in Example 66 (2), the title compound (280 mg) was obtained asa pale-yellow solid.

[0508]¹H-NMR(DMSO-d₆)δ1.88-1.97(1H,m), 2.46-2.58(1H,m),2.88(1H,dd,J=12.9,4.0 Hz), 2.99(1H,t,J=6.3 Hz), 3.09(1H,t,J=6.3 Hz),3.23(1H,d,J=12.9 Hz), 3.57-3.76(1.5H,m), 3.84-3.99(1.5H,m),4.42(0.5H,d,J=9.5 Hz), 4.48-4.57(1H,m), 4.72(0.5H,d,J=9.5 Hz),5.33-5.38(1H,m), 8.01(2H,d,J=8.3 Hz), 8.07(2H,d,J=8.3 Hz).

Example 68

[0509] Synthesis of3-((2S,4S)-4-anilino-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[0510] (1) The title compound (501 mg) of Reference Example 12, aniline(0.20 mL) and acetic acid (0.10 mL) were dissolved in methanol (10 mL),and the mixture was stirred at room temperature for 1.5 hr. Sodiumcyanoborohydride (145 mg) was added to the reaction mixture and themixture was stirred for 2 hr. The reaction mixture was evaporated underreduced pressure. Saturated aqueous sodium hydrogencarbonate solutionwas added to the residue and the mixture was extracted with ethylacetate. The extract was washed with brine and dried. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography and crystallized from diethyl ether to give3-((2S,4S)-4-anilino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(156 mg) as white crystals.

[0511] (2) The above-mentioned compound (142 mg) was dissolved in ethylacetate (2 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) wasadded thereto. The mixture was stirred at room temperature for 12 hr.The precipitated solid was collected by filtration to give the titlecompound (89 mg) as a white powder.

[0512]¹H-NMR(DMSO-d₆)δ1.64-1.78(1H,m), 2.84-2.97(1H,m), 3.00-3.19(3H,m),3.43-3.55(1H,m), 3.60-4.20(5H,m), 4.41-4.76(3H,m), 6.56-6.67(3H,m),7.13(2H,t,J=7.2 Hz), 8.79(1H,brs), 10.29(1H,brs).

Example 69

[0513] Synthesis of3-[(2S,4S)-4-(4-aminophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride The title compound (200 mg) of Example 55 was dissolved inethanol (10 mL), and 4 mol/L hydrochloric acid-1,4-dioxane (0.28 mL) and10% palladium/carbon (100 mg) were added. The mixture was stirred undera hydrogen atomosphere (1 atm) at room temperature for 18 hr. Thereaction mixture was filtrated and the filtrate was concentrated underreduced pressure, and the obtained solid was washed with ethanol to givethe title compound (13 mg) as a white powder.

[0514]¹H-NMR(DMSO-d₆)δ1.58-1.80(1H,m), 2.83-3.00(1H,m), 3.00-3.20(3H,m),3.60-3.90(3H,m), 4.08-4.25(1H,m), 4.39-4.79(3H,m), 6.67(2H,d,J=8.7 Hz),7.15(2H,d,J=8.7 Hz), 8.81(1H,brs), 10.00(3H,brs), 10.25(1H,brs).

Example 70

[0515] Synthesis of3-[(2S,4S)-4-(p-anisidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0516] (1) The title compound (450 mg) of Reference Example 12,p-anisidine (222 mg) and acetic acid (0.09 mL) were dissolved in1,2-dichloroethane (8 mL), and sodium triacetoxyborohydride (636 mg) wasadded thereto. The mixture was stirred at room temperature for 3 hr.Saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with brine and dried. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelchromatography to give3-[(2S,4S)-4-(p-anisidino)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(515 mg) as a white solid.

[0517] (2) The above-mentioned compound (448 mg) was dissolved in ethylacetate (10 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.4 mL) wasadded thereto. The mixture was stirred at room temperature for 13 hr.The precipitated solid was collected by filtration to give the titlecompound (223 mg) as a white powder.

[0518]¹H-NMR(DMSO-d₆)δ1.77-1.90(1H,m), 2.77-2.89(1H,m), 3.00-3.14(3H,m),3.20-4. 20(1H,m), 3.60-4.20(6H,m), 4.40-4.72(3H,m), 6.87(4H,s),8.84(1H,brs), 10.33(1H,brs).

Example 71

[0519] Synthesis of3-[(2S,4S)-4-(4-chlorophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0520] (1) Using the title compound (450 mg) of Reference Example 12 andp-chloroaniline (230 mg), and in the same manner as in

Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-chlorophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(415 mg) was obtained as an oil.

[0521] (2) Using the above-mentioned compound (412 mg), and in the samemanner as in Example 70 (2) the title compound (297 mg) was obtained asa white powder.

[0522]¹H-NMR(DMSO-d₆)δ1.63-1.78(1H,m), 2.84-2.97(1H,m), 3.00-3.17(3H,m),3.5-3.92(3H,m), 4.07-4.18(1H,m), 4.40-4.73(3H,m), 6.62(2H,d,J=8.8 Hz),7.15(2H,d,J=8.8 Hz), 8.86(1H,brs), 10.23(1H,brs).

Example 72

[0523] Synthesis of3-[(2S,4S)-4-(2-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0524] (1) The title compound (904 mg) of Reference Example 10,diisopropylethylamine (1.57 mL) and 3-chloro-4-fluorobenzonitrile (467mg) were dissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture wasstirred at 80° C. for 8 hr. The reaction solution wag added to saturatedaqueous sodium hydrogencarbonate solution, extracted with ethyl acetate.The extract was dried and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(460 mg) as a white solid.

[0525] (2) The above-mentioned compound (395 mg) was dissolved in ethylacetate (1.8 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.13 mL)was added thereto. The mixture was stirred at room temperature for 4 hr,and the precipitated solid was collected by filtration to give the titlecompound (177 mg) as a white powder.

[0526]¹H-NMR(DMSO-d₆)δ1.80-1.99(1H,m), 2.82-3.17(3H,m), 3.25-3.94(4H,m),4.36-4.54(2H,m), 4.54-4.80(2H,m), 6.42(1H,d,J=7.8 Hz), 6.93(1H,d,J=8.7Hz), 7.64(1H,dd,J=8.4,1.8 Hz), 7.82(d,J=1.8 Hz).

Example 73

[0527] Synthesis of3-[(2S,4S)-4-(3-chloro-4-methoxyphenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0528] (1) Using the title compound (450 mg) of Reference Example 12 and3-chloro-4-methoxyaniline (284 mg), and in the same manner as in Example70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-methoxyphenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(569 mg) was obtained as an oil.

[0529] (2) Using the above-mentioned compound (561 mg), and in the samemanner as in Example 70 (2), the title compound (429 mg) was obtained asa pale-brown powder.

[0530]¹H-NMR(DMSO-d₆)δ1.62-1.76(1H,m), 2.82-2.95(1H,m), 3.00-3.18(3H,m),3.5-3.92(6H,m), 4.07-4.18(1H,m), 4.40-4.73(3H,m), 6.61(1H,dd,J=8.8,2.7Hz), 6.75(1H,d,J=2.7 Hz), 6.98(1H,d,J=8.8 Hz), 8.80(1H,brs),10.15(1H,brs).

Example 74

[0531] Synthesis of3-[(2S,4S)-4-(3,4-methylenedioxyphenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0532] (1) Using the title compound (450 mg) of Reference Example 12 and3,4-methylenedioxyaniline (249 mg), and in the same manner as in Example70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3,4-methylenedioxyphenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(553 mg) was obtained as a pale-brown-reddish solid.

[0533] (2) Using the above-mentioned compound (549 mg), and in the samemanner as in Example 70 (2), the title compound (457 mg) as obtained asa pale-brown-reddish powder.

[0534]¹H-NMR(DMSO-d₆)δ1.72-1.85(1H,m), 2.820-2.93(1H,m),3.00-3.28(3H,m), 3.45-3.57(1H,m), 3.60-3.95(2H,m), 4.08-4.20(1H,m),4.42-4.75(3H,m), 5.92(2H,s), 6.25-6.32(1H,m), 6.53(1H,s),6.76-6.83(1H,m), 8.89(1H,brs), 10.36(1H,brs).

Example 75

[0535] Synthesis of3-[(2S,4S)-4-(5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0536] (1) The title compound (904 mg) of Reference Example 10,diisopropylethylamine (1.57 mL) and 2-chloro-5-trifluoromethylpyridine(545 mg) were dissolved in N-methyl-2-pyrrolidone (9 mL), and themixture was stirred at 80° C. for 18 hr. The reaction solution was addedto saturated aqueous sodium hydrogencarbonate solution, and extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(143 mg).

[0537] (2) The above-mentioned compound (143 mg) was dissolved in ethylacetate (0.64 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.32 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration to give the titlecompound (65 mg) as a brown powder.

[0538]¹H-NMR(DMSO-d₆)δ1.71-1.93(1H,m), 2.80-2.98(1H,m), 3.00-3.28(3H,m),3.34-3.99(3H,m), 4.40-4.80(4H,m), 6.68(1H,d,J=9.0 Hz),7.74(1H,dd,J=8.7,2.4 Hz), 7.83(1H,brs), 8.35(1H,d,J=1.2 Hz),8.91(1H,brs), 10.22(1H,brs).

Example 76

[0539] Synthesis of3-[(2S,4S)-4-(6-cyano-5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0540] (1) 2-Chloro-5-trifluoromethylpyridine (5 g) was dissolved inchloroform (150 mL) and m-chloroperbenzoic acid (14.3 g) was addedthereto. The mixture was stirred at 60° C. for 30 hr. Aqueous sodiumthiosulfate solution and saturated aqueous sodium hydrogencarbonatesolution were added to the reaction mixture, and after stirring, themixture was extracted with chloroform. The extract was washedsuccessively with saturated aqueous sodium hydrogencarbonate solutionand brine, and dried. The solvent was evaporated under reduced pressureand the residue was purified by silica gel chromatography to give2-chloro-5-trifluoromethylpyridine 1-oxide (0.64 g).

[0541] (2) The above-mentioned compound (610 mg) was dissolved inacetonitrile (5 mL), and triethylamine (0.861 mL) and trimethylsilylcyanide (1.16 mL) were added thereto. The mixture was refluxed for 4 hr.Saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with brine and the solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatographyto give 6-chloro-3-trifluoromethylpyridine-2-carbonitrile (401 mg) as ared oil.

[0542] (3) The above-mentioned compound (381 mg), the title compound(556 mg) of Reference Example 10 and diisopropylethylamine (0.96 mL)were dissolved in N-methyl-2-pyrrolidone (6 mL), and the mixture wasstirred at room temperature for 18 hr. The reaction solution was addedto saturated aqueous sodium hydrogencarbonate solution and extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(6-cyano-5-trifluoromethyl-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(509 mg) as a colorless transparent oil.

[0543] (4) The above-mentioned compound (481 mg) was dissolved in ethylacetate (2.04 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.02 mL)was added thereto. The mixture was stirred at room temperature for 8 hr.The reaction solvent was evaporated under reduced pressure, and theobtained solid was washed with ethyl acetate to give the title compound(272 mg) as a white powder.

[0544]¹H-NMR(DMSO-d₆)δ1.71-1.95(1H,m), 2.77-2.98(1H,m), 2.99-3.27(3H,m),3.48-3.99(3H,m), 4.40-4.80(4H,m), 6.96(1H,d,J=9.0 Hz), 7.93(1H,d,J=9.0Hz), 8.40(1H,t,J=6.0 Hz), 9.55(1H,brs).

Example 77

[0545] Synthesis of3-[(2S,4S)-4-(5,6-dicyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0546] (1) 2-Chloropyridine-5-carbonitrile (7.01 g) was dissolved inacetonitrile (70 mL), and urea hydrogen peroxide addition compound (10g) was added. Trifluoroacetic anhydride was added dropwise to thereaction mixture under ice-cooling and the mixture was stirred at roomtemperature for 18 hr. The reaction mixture was added to aqueous sodiumthiosulfate solution and the mixture was extracted with chloroform. Theextract was washed successively with saturated aqueous sodiumhydrogencarbonate solution and brine and dried. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel chromatography to give 2-chloro-5-cyanopyridine 1-oxide (0.779 g) asa white solid.

[0547] (2) Using the above-mentioned compound (779 mg), and in the samemanner as in Example 76 (2), 6-chloro-2,3-dicyanopyridine (198 mg) wasobtained as a brown solid.

[0548] (3) Using the above-mentioned compound (196 mg) and the titlecompound (361 mg) of Reference Example 10, and in the same manner as inExample 76 (3),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5,6-dicyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(338 mg) was obtained as a white solid.

[0549] (4) The above-mentioned compound (338 mg) was dissolved in ethylacetate (1.58 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.79 mL)was added thereto. The mixture was stirred at room temperature for 6 hr.The precipitated solid was collected by filtration to give the titlecompound (178 mg) as a pale-yellow powder.

[0550]¹H-NMR(DMSO-d₆)δ1.71-1.98(1H,m), 2.80-3.00(1H,m), 3.00-3.24(3H,m),3.49-4.00(3H,m), 4.39-4.90(3H,m), 6.94(1H,d,J=9.0 Hz), 7.97(1H,d,J=8.7Hz), 8.70(1H,brs), 9.55(2H,brs).

Example 78

[0551] Synthesis of3-[(2S,4S)-4-(3-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0552] (1) Using the title compound (3.62 g) of-Reference Example 10 and3-cyanobenzaldehyde (1.57 g), and in the same manner as in Example 63(1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(2.01 g) was obtained.

[0553] (2) The above-mentioned compound (313 mg) was dissolved in ethylacetate (1.50 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.94 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration to give the titlecompound (217 mg) as a white powder.

[0554]¹H-NMR(DMSO-d₆)δ2.09-2.30(1H,m), 2.87-3.01(1H,m), 3.07(1H,t,J=6.3Hz), 3.15(1H,t,J=6.0 Hz), 3.50-4.05(5H,m), 4.27(2H,s), 4.40-4.78(3H,m),7.67(1H,t,J=7.8 Hz), 7.84-8.00(2H,m), 8.10(1H,s), 10.28(3H,brs).

Example 79

[0555] Synthesis of3-[(2S,4S)-4-(4-trifluoromethylphenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0556] (1) Using the title compound (1.81 g) of Reference Example 10 and4-(trifluoromethyl)benzaldehyde (1.05 g), and in the same manner as inExample 63 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-trifluoromethylphenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1.69 g) was obtained.

[0557] (2) The above-mentioned compound (488 mg) was dissolved in ethylacetate (2.12 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.33 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the precipitated solid was collected by filtration to give the titlecompound (375 mg) as a white powder.

[0558]¹H-NMR(DMSO-d₆)δ2.10-2.32(1H,m), 2.86-3.00(1H,m), 2.50(1H,t,J=1.8Hz), 2.51(1H,t,J=1.8 Hz), 3.50-4.02(5H,m), 4.32(2H,s), 4.41-4.80(3H,m),7.78-7.92(4H,m), 10.35(3H,brs).

Example 80

[0559] Synthesis of3-{(2S,4S)-4-[bis(4-cyanophenylmethyl)]amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0560] (1) The title compound (0.904 g) of Reference Example 10,4-cyanobenzyl bromide (1.29 g) and diisopropylethylamine (1.57 mL) weredissolved in N-methyl-2-pyrrolidone (9 mL), and the mixture was stirredat room temperature for 18 hr. The reaction mixture was added tosaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[bis(4-cyanophenylmethyl)]amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.27 g).

[0561] (2) The above-mentioned compound (1.13 g) was dissolved in ethylacetate (4.24 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.65 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the precipitated solid was collected by filtration to give the titlecompound (444 mg) as a white powder.

[0562]¹H-NMR(DMSO-d₆)δ1.81-1.94(1H,m), 2.57-2.79(1H,m),3.00-3.95(11H,m), 4.39-4.75(3H,m), 7.55(4H,d,J=8.1 Hz), 7.79(4H,d,J=8.1Hz), 8.78(1H,brs), 10.19(1H,brs).

Example 81

[0563] Synthesis of3-[(2S,4S)-4-(4-imidazolylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrihydrochloride

[0564] (1) Using the title compound (904 mg) of Reference Example 10 and4-imidazolecarboxyaldehyde (288 mg), and in the same manner as inExample 63 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-imidazolylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(221 mg) was obtained.

[0565] (2) The above-mentioned compound (221 mg) was dissolved in ethylacetate (1.16 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.72 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration, and washed withethanol to give the title compound (7.7 mg) as a white powder.

[0566]¹H-NMR(DMSO-d₆)δ2.04-2.26(1H,m), 2.88-4.10(8H,m), 4.25-4.80(5H,m),7.82(1H,s), 9.07(1H,s).

Example 82

[0567] Synthesis of3-{(2S,4S)-4-[N-benzyl-N-(5-cyano-2-pyridyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinehydrochloride

[0568] (1)3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine[product of Example 58(1)] (305 mg) was dissolved in DMF (10 mL), andpotassium tert-butoxide (93 mg) was added under ice cooling. Afterstirring the mixture for 10 min, benzyl bromide (94 μl) was added, andthe mixture was stirred at room temperature for 3 days. 10% citric acidsolution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed successively withsaturated aqueous sodium hydrogencarbonate solution and brine, anddried. The solvent was evaporated under reduced pressure and the residuewas purified by silica gel chromatography to give3-{(2S,4S)-4-[N-benzyl-N-(5-cyano-2-pyridyl)amino]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(202 mg) as a pale-yellow solid.

[0569] (2) The above-mentioned compound (196 mg) was dissolved in ethylacetate (2 ml) and 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) wasadded thereto. The mixture was stirred at room temperature for 17 hr.The precipitated solid was collected by filtration to give the titlecompound (112 mg) as a pale-yellow powder.

[0570]¹H-NMR(DMSO-d₆)δ1.91-1.99(1H,m), 2.69-2.76(1H,m), 3.00-3.11(2H,m),3.28-3.34(1H,m), 3.41-3.48(1H,m), 3.58-3.90(2H,m), 4.41-4.47(1H,m),4.58-4.81(4H,m), 5.43-5.48(1H,m), 6.65(1H,d,J=9.0 Hz), 7.17-7.38(5H,m),7.88(1H,dd,J=9.0,2.1 Hz), 8.54(1H,d,J=2.1 Hz), 8.84(1H,brs),10.21(1H,brs).

Example 83

[0571] Synthesis of3-[(2S,4S)-4-(1-indolyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0572] (1) The title compound (950 mg) of Reference Example 13 andthiazolidine (0.27 mL) were dissolved in DMF (20 mL), and HOBT (666 mg)and EDC hydrochloride (666 mg) were added successively. The mixture wasstirred at room temperature for 4 hr. The reaction mixture was added tosaturated aqueous sodium hydrogencarbonate solution, and extracted withethyl acetate. The extract was washed with brine and dried. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(978 mg) as a white solid.

[0573] (2) Using the above-mentioned compound (665 mg), and in the samemanner as in Example 68 (2), the title compound (486 mg) was obtained asa red powder.

[0574]¹H-NMR(DMSO-d₆)δ2.14-2.28(1H,m), 2.98-3.18(4H,m), 3.4-3.97(3H,m),4.43-4.87(3H,m), 5.38-5.55(1H,m), 6.55(1H,d,J=3.3 Hz), 7.07(1H,t,J=7.1Hz), 7.20(1H,d,J=7.1 Hz), 7.48-7.63(3H,m), 9.25(1H,brs), 10.45(1H,brs).

Example 84

[0575] Synthesis of3-[(2S,4S)-4-(1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0576] (1) Using the title compound (601 mg) of Reference Example 12 andindoline (0.27 mL), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(460 mg) was obtained as a white solid.

[0577] (2) Using the above-mentioned compound (436 mg), and in the samemanner as in Example 70 (2), the title compound (373 mg) was obtained asa white powder.

[0578]¹H-NMR(DMSO-d₆)δ1.83-1.97(1H,m), 2.62-2.77(1H,m), 2.88(2H,t,J=8.2Hz), 3.04(1H,t,J=7.0 Hz), 3.12(1H,t,J=6.2 Hz), 3.20-3.95(6H,m),4.40-4.78(4H,m), 6.55-6.68(2H,m), 6.98-7.09(2H,m), 8.84(1H,brs),10.31(1H,brs).

Example 85

[0579] Synthesis of1-[(2S,4S)-4-(1-indolinyl)-2-pyrrolidinylcarbonyl]pyrrolidinedihydrochloride

[0580] (1) Using the title compound (565 mg) of Reference Example 14 andindoline (0.27 mL), and in the same manner as in Example 70 (1),1-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-indolinyl)-2-pyrrolidinylcarbonyl]pyrrolidine(653 mg) was obtained as a white solid.

[0581] (2) Using the above-mentioned compound (648 mg), and in the samemanner as in Example 70 (2), the title compound (491 mg) was obtained asa white powder.

[0582]¹H-NMR(DMSO-d₆)δ1.75-1.97(5H,m), 2.60-2.72(1H,m), 2.88(2H,t,J=8.2Hz), 3.218-3.60(8H,m), 4.40-4.55(2H,m), 6.56-6.67(2H,m),6.98-7.09(2H,m), 8.75(1H,brs), 10.41(1H,brs).

Example 86

[0583] Synthesis of3-[(2S,4S)-4-(5-nitro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0584] (1) Using the title compound (450 mg) of Reference Example 12 and5-nitroindoline (295 mg), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-nitro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(153 mg) was obtained as an oil.

[0585] (2) Using the above-mentioned compound (153 mg), and in the samemanner as in Example 70 (2), the title compound (116 mg) was obtained asa yellow powder.

[0586]¹H-NMR(DMSO-d₆)δ1.92-2.06(1H,m), 2.67-2.80(1H,m), 3.00-3.17(4H,m),3.27-3.94(6H,m), 4.42-4.78(4H,m), 6.62(1H,d,J=8.9 Hz), 7.87(1H,d,J=2.3Hz), 8.04(1H,dd,J=8.9,2.3 Hz), 9.1(1H,brs), 10.2(1H,brs).

Example 87

[0587] Synthesis of3-[(2S,4S)-4-(6-nitro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0588] (1) Using the title compound (450 mg) of Reference Example 12 and6-nitroindoline (296 mg), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(6-nitro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(188 mg) was obtained as an oil.

[0589] (2) Using the above-mentioned compound (188 mg), and in the samemanner as in Example 70 (2), the title compound (80 mg) was obtained asa brown-reddish powder.

[0590]¹H-NMR(DMSO-d₆)δ1.84-2.00(1H,m), 2.64-2.77(1H,m), 3.00-3.17(4H,m),3.22-3.92(6H,m), 4.41-4.77(4H,m), 7.22-7.32(2H,m), 7.51(1H,dd,J=7.9,1.9Hz), 8.94(1H,brs), 10.12(1H,brs).

Example 88

[0591] Synthesis of3-[(2S,4S)-4-(5-methoxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0592] (1) Using the title compound (751 mg) of Reference Example 12 and5-methoxyindoline (410 mg), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-methoxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1010 mg) was obtained as a white solid.

[0593] (2) Using the above-mentioned compound (326 mg), and in the samemanner as in Example 70 (2), the title compound (262 mg) was obtained asa white powder.

[0594]¹H-NMR(DMSO-d₆)δ1.80-1.95(1H,m), 2.62-2.75(1H,m), 2.86(2H,t,J=7.9Hz), 3.04(1H,t,J=7.0 Hz), 3.12(1H,t,J=6.2 Hz), 3.17-3.52(4H,m),3.65(3H,s), 3.66-4.08(6H,m), 4.28-4.77(4H,m), 6.54(1H,d,J=8.5 Hz),6.63(1H,dd,J=8.5,2.4 Hz), 6.75(1H,d,J=2.4 Hz), 8.83(1H,brs),10.40(1H,brs).

Example 89

[0595] Synthesis of3-[(2S,4S)-4-(5-hydroxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0596] (1) Using the title compound (872 mg) of Reference Example 12 and5-hydroxyindoline (390 mg), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-hydroxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(538 mg) was obtained as a pale-brown solid.

[0597] (2) Using the above-mentioned compound (163 mg), and in the samemanner as in Example 70 (2), the title compound (101 mg) was obtained asa white powder.

[0598]¹H-NMR(DMSO-d₆)δ1.85-2.00(1H,m), 2.63-2.78(1H,m), 2.88(2H,t,J=7.7Hz), 3.04(1H,t,J=6.6 Hz), 3.12(1H,t,J=6.2 Hz), 3.24-3.95(6H,m),4.27-4.76(4H,m), 6.51-6.68(3H,m), 8.96(1H,brs), 10.43(1H,brs).

Example 90

[0599] Synthesis of3-[(2S,4S)-4-(5-acetoxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0600] (1) Using3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-hydroxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine[product of Example 89 (1), 174 mg] and acetyl chloride (50 μL), and inthe same manner as in Example 50 (1),3-[(2S,4S)-4-(5-acetoxy-1-indolinyl)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(136 mg) was obtained as an oil.

[0601] (2) Using the above-mentioned compound (136 mg), and in the samemanner as in Example 70 (2), the title compound (77 mg) was obtained asa pale-brown powder.

[0602]¹H-NMR(DMSO-d₆)δ1.83-1.96(1H,m), 2.20(3H,s), 2.63-2.77(1H,m),2.89(2H,t,J=8.1 Hz), 3.05(1H,t,J=6.8 Hz), 3.12(1H,t,J=6.2 Hz),3.18-3.53(4H,m), 3.61-3.93(2H,m), 4.36-4.77(4H,m), 6.56(1H,d,J=8.4 Hz),6.76(1H,dd,J=8.4,2.3 Hz), 6.83(1H,d,J=2.3 Hz), 8.91(1H,brs),10.19(1H,brs).

Example 91

[0603] Synthesis of3-[(2S,4S)-4-(5-benzoyloxy-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0604] (1) Using the product (199 mg) of Example 89 (1) and benzoylchloride (83 μL), and in the same manner as in Example 50 (1),3-[(2S,4S)-4-(5-benzoyloxy-1-indolinyl)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(173 mg) was obtained as a pale-brown solid.

[0605] (2) Using the above-mentioned compound (173 mg), and in the samemanner as in Example 7.0 (2), the title compound (116 mg) was obtainedas a pale-brown powder.

[0606]¹H-NMR(DMSO-d₆)δ1.84-1.98(1H,m), 2.66-2.78(1H,m), 2.93(2H,t,J=8.3Hz), 3.05(1H,t,J=6.7 Hz), 3.13(1H,t,J=6.2 Hz), 3.23-3.56(4H,m),3.6-3.95(2H,m), 4.42-4.78(4H,m), 6.62(1H,d,J=8.4 Hz),6.93(1H,dd,J=8.4,2.2 Hz), 6.99(1H,d,J=2.2 Hz), 7.60(2H,t,J=7.5 Hz),7.74(1H,t,J=7.5 Hz), 8.10(2H,d,J=7.5 Hz), 8.93(1H,brs), 10.37(1H,brs).

Example 92

[0607] Synthesis of3-[(2S,4S)-4-(5-fluoro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0608] (1) Using the title compound (496 mg) of Reference Example 12 and5-fluoroindoline (200 mg), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-fluoro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(492 mg) was obtained as a pale-brown solid.

[0609] (2) Using the above-mentioned compound (487 mg), and in the samemanner as in Example 70 (2), the title compound (357 mg) was obtained asa white powder.

[0610]¹H-NMR(DMSO-d₆)δ1.80-1.95(1H,m), 2.62-2.75(1H,m), 2.88(2H,t,J=8.2Hz), 3.04(1H,t,J=7.0 Hz), 3.11(1H,t,J=6.2 Hz), 3.18-3.52(4H,m),3.60-3.94(2H,m), 4.35-4.78(4H,m), 6.55(1H,dd,J=8.8,4.3 Hz),6.85(1H,td,J=8.8,2.6 Hz), 6.94(1H,dd,J=8.5,2.6 Hz), 8.90(1H,brs),10.44(1H,brs).

Example 93

[0611] Synthesis of3-[(2S,4S)-4-(5-chloro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0612] (1) Using the title compound (665 mg) of Reference Example 12 and5-chloroindoline (340 mg), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-chloro-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(393 mg) was obtained as a white solid.

[0613] (2) Using the above-mentioned compound (389 mg), and in the samemanner as in Example 70 (2), the title compound (242 mg) was obtained asa white powder.

[0614]¹H-NMR(DMSO-d₆)δ1.81-1.95(1H,m), 2.62-2.74(1H,m), 2.90(2H,t,J=8.3Hz), 3.04(1H,t,J=7.1 Hz), 3.12(1H,t,J=6.2 Hz), 3.18-3.52(4H,m),3.60-3.94(2H,m), 4.38-4.77(4H,m), 6.57(1H,d,J=8.3 Hz), 7.03-7.11(2H,m),8.86(1H,brs), 10.38(1H,brs).

Example 94

[0615] Synthesis of3-[(2S,4S)-4-(5-bromo-1-indolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0616] (1) Using the title compound (0.901 g) of Reference Example 12and 5-bromoindoline (0.713 g), and in the same manner as in Example 70(1),3-[(2S,4S)-4-(5-bromo-1-indolinyl)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1.31 g) was obtained as a white solid.

[0617] (2) Using the above-mentioned compound (340 mg), and in the samemanner as in Example 70 (2), the title compound (251 mg) was obtained asa pale-red powder.

[0618]¹H-NMR(DMSO-d₆),δ1.82-1.96(1H,m), 2.62-2.74(1H,m), 2.91(2H,t,J=8.3Hz), 3.04(1H,t,J=7.0 Hz), 3.12(1H,t,J=6.2 Hz), 3.18-3.54(4H,m),3.62-3.93(2H,m), 4.37-4.77(4H,m), 6.53(1H,d,J=8.1 Hz), 7.15-7.24(2H,m),8.91(1H,brs), 10.27(1H,brs).

Example 95

[0619] Synthesis of3-[(2S,4S)-4-(1,2,3,4-tetrahydro-1-quinolyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0620] (1) Using the title compound (450 mg) of Reference Example 12 and1,2,3,4-tetrahydroquinoline (0.23 mL), and in the same manner as inExample 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1,2,3,4-tetrahydro-1-quinolyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(100 mg) was obtained as an oil.

[0621] (2) Using the above-mentioned compound (100 mg), and in the samemanner as in Example 70 (2), the title compound (60 mg) was obtained asa pale-brown-reddish powder.

[0622]¹H-NMR(DMSO-d₆)δ1.76-1.97(3H,m), 2.59-2.73(3H,m), 3.02-3.5(6H,m),3.62-3.94(2H,m), 4.42-4.86(4H,m), 6.57(1H,d,J=7.2 Hz), 6.80(1H,d,J=8.3Hz), 6.92(1H,d,J=7.2 Hz), 6.97-7.07(1H,m), 8.84(1H,brs), 10.04(1H,brs).

Example 96

[0623] Synthesis of3-[(2S,4S)-4-(2-isoindolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine 2trifluoroacetate

[0624] (1) The title compound (1.49 g) of Reference Example 10 wasdissolved in DMF (50 mL), and potassium carbonate (2.04 g) andα,α′-dibromo-o-xylene (1.37 g) were added thereto. The mixture wasstirred at room temperature for 18 hr. Water was added to the reactionmixture and the mixture was extracted with chloroform. The extract waswashed with brine and dried. The solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-isoindolinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1.26 g) as a pale-brown solid.

[0625] (2) Using the above-mentioned compound (910 mg), and in the samemanner as in Example 1, the title compound (730 mg) was obtained as abrown powder.

[0626]¹H-NMR(DMSO-d₆)δ2.05-2.14(1H,m), 2.88-2.96(1H,m), 3.05-3.17(2H,m),3.42-4.02(5H,m), 4.44-4.75(7H,m), 7.31-7.37(4H,m).

Example 97

[0627] Synthesis of3-[(2S,4S)-4-(N-methylanilino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0628] (1) Using the title compound (450 mg) of Reference Example 12 andN-methylaniline (0.22 mL), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(N-methylanilino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(274 mg) was obtained as a white solid.

[0629] (2) Using the above-mentioned compound (216 mg), and in the samemanner as in Example 70 (2), the title compound (149 mg) was obtained asa white powder.

[0630]¹H-NMR(DMSO-d₆)δ1.83-1.98(1H,m), 2.56-2.69(1H,m), 2.82(3H,s),3.05(1H,t,J=6.9 Hz), 3.11(1H,t,J=6.2 Hz), 3.20-3.32(1H,m),3.36-3.50(1,m), 3.62-4.0(4H,m), 4.43-4.82(4H,m), 6.85(1H,t,J=7.5 Hz),7.02(1H,d,J=7.5 Hz), 7.27(1H,t,J=7.5 Hz), 8.89(1H,brs), 10.44(1H,brs).

Example 98

[0631] Synthesis of3-{(2S,4S)-4-[N-(5-cyano-2-pyridyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinehydrochloride

[0632] (1) Using the product (313 mg) of Example 58 (1) and methyliodide 53 μL, and in the same manner as in Example 82 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(5-cyano-2-pyridyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(200 mg) was obtained as a white powder.

[0633] (2) Using the above-mentioned compound (198 mg), and in the samemanner as in Example 5 (2), the title compound (165 mg) was obtained asa white powder.

[0634]¹H-NMR(DMSO-d₆)δ1.91-1.99(1H,m), 2.62-2.70(1H,m), 2.98(3H,s),3.00-3.13(2H,m), 3.30-3.34(2H,m), 3.65-3.93(2H,m), 4.45-4.77(3H,m),5.51-5.57(1H,m), 6.84(1H,d,J=9.0 Hz), 7.94(1H,dd,J=9.0,2.4 Hz),8.52(1H,d,J=2.4 Hz), 8.93(1H,brs), 10.22(1H,brs).

Example 99

[0635] Synthesis of3-{(2S,4S)-4-[N-(3-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0636] (1) Using3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine[product of Example 78 (1), 313 mg], and in the same manner as inExample 64 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(3-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(598 mg) was obtained as an oil.

[0637] (2) The above-mentioned compound (571 mg) was dissolved in ethylacetate (2.65 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.66 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitated solid was collected by filtration to give the titlecompound (377 mg) as a white powder.

[0638]¹H-NMR(DMSO-d₆)δ2.20-2.42(1H,m), 2.57(3H,brs), 2.80-3.20(3H,m),3.55-4.10(5H,m), 4.20-4.85(5H,m), 7.68(1H,t,J=7.8 Hz), 7.88-8.05(2H,m),8.14(1H,brs), 9.12(1H,brs), 10.70(1H,brs).

Example 100

[0639] Synthesis of3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(2-propyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0640] (1) Using the product (833 mg) of Example 63 (1) and acetone, andin the same manner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(2-propyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(818 m) was obtained.

[0641] (2) The above-mentioned compound (792 mg) was dissolved in ethylacetate (3.47 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.16 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the precipitated solid was collected by filtration to give the titlecompound (637 mg) as a white powder.

[0642]¹H-NMR(DMSO-d₆)δ0.90-1.60(6H,m), 1.95-2.45(1H,m), 2.65-3.20(3H,m),3.40-4.90(11H,m), 7.50-8.30(4H,m).

Example 101

[0643] Synthesis of3-{(2S,4S)-4-[N-butyl-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0644] (1) Using the product (833 mg) of Example 63 (1) andn-butyraldehyde (216 mg), and in the same manner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-butyl-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(837 mg) was obtained.

[0645] (2) The above-mentioned compound (830 mg) was dissolved in ethylacetate (3.51 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.20 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the precipitated solid was collected by filtration to give the titlecompound (607 mg) as a pale-yellow powder.

[0646]¹H-NMR(DMSO-d₆)δ0.80(3H,t,J=7.2 Hz), 1.18(2H,quint,J=6.9 Hz),1.30-1.90(2H,m), 2.10-2.50(1H,m), 2.60-3.24(5H,m), 3.54-4.87(9H,m),7.60-8.20(4H,m).

Example 102

[0647] Synthesis of3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(2-hydroxyethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0648] (1) The product (1.67 g) of Example 63 (1) was dissolved inN-methyl-2-pyrrolidone (12 mL), and 2-bromoethanol (1.42 mL) anddiisopropylethylamine (2.09 mL) were added thereto. The mixture wasstirred at 80° C. for 2 days. The reaction mixture was added tosaturated aqueous sodium hydrogencarbonate solution and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(2-hydroxyethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.480 g).

[0649] (2) The above-mentioned compound (480 mg) was dissolved in ethylacetate (2.08 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.04 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the precipitated solid was collected by filtration to give the titlecompound (351 mg) as a brown powder.

[0650]¹H-NMR(DMSO-d₆)δ1.85-1.97(1H,m), 2.02-2.33(2H,m),2.70-4.80(14H,m), 7.60-8.00(4H,m), 9.00(1H,brs), 10.50(1H,brs).

Example 103

[0651] Synthesis of3-{(2S,4S)-4-[N-(carboxymethyl)-N-(5-cyano-2-pyridyl)amino]-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrifluoroacetate

[0652] (1) Using the product (461 mg) of Example 58 (1) and tert-butylbromoacetate (202 μL), and in the same manner as in Example 82 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(tert-butoxycarbonylmethyl)-N-(5-cyano-2-pyridyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(344 mg) was obtained as a pale-yellow powder.

[0653] (2) Using the above-mentioned compound (340 mg), and by thesynthesis in the same manner as in Example 1 and purification by HPLC,the title compound (118 mg) was obtained as a white solid.

[0654]¹H-NMR(500 MHz,DMSO-d₆)δ1.93-1.98(1H,m), 2.66-2.69(1H,m),3.04-3.12(2H,m), 3.27-3.31(1H,m), 3.40-3.45(1H,m), 3.62-3.87(2H,m),4.32(2H,s), 4.44-4.71(3H,m), 5.23(1H,m), 6.81(1H,d,J=7.3 Hz),7.95(1H,dd,J=7.3,2.3 Hz), 8.51(1H,d,J=2.3 Hz).

Example 104

[0655] Synthesis of3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(ethoxycarbonylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0656] (1) The product (0.833 g) of Example 63 (1) was dissolved inN-methyl-2-pyrrolidone (6 mL), and ethyl bromoacetate (0.333 mL) anddiisopropylethylamine (1.05 mL) were added thereto. The mixture wasstirred at room temperature for 18 hr. The reaction mixture was added tosaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(ethoxycarbonylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.01 g) as an oil.

[0657] (2) The above-mentioned compound (976 mg) was dissolved in ethylacetate (3.88 mL) and 4 mol/L hydrochloric acid-ethyl acetate (2.43 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the precipitated solid was collected by filtration to give the titlecompound (630 mg) as a white powder.

[0658]¹H-NMR(DMSO-d₆)δ1.18-(3H,t,J=7.1 Hz), 1.67-1.90(1H,m),2.56-2.75(1H,m), 2.94-3.22(3H,m), 3.25-4.00(8H,m), 4.07(2H,q,J=7.1 Hz),4.34-4.78(3H,m), 7.54(2H,d,J=8.2 Hz), 7.81(2H,d,J=8.2 Hz), 8.80(1H,brs),10.40(1H,brs).

Example 105

[0659] Synthesis of3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(isopropoxycarbonylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0660] (1) Using the product (0.833 g) of Example 63 (1) and isopropylbromoacetate (0.259 mL), and in the same manner as in Example 104 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(isopropoxycarbonylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.967 g) was obtained as an oil.

[0661] (2) The above-mentioned compound (966 mg) was dissolved in ethylacetate (3.74 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.87 mL)was added thereto. The mixture was stirred at room temperature for 8 hr.The precipitated solid was collected by filtration to give the titlecompound (641 mg) as a white powder.

[0662]¹H-NMR(DMSO-d₆)δ1.18(6H,d,J=6.0 Hz), 1.65-1.84(1H,m),2.55-2.74(1H,m), 2.95-3.16(3H,m), 3.22-3.47(3H,m), 3.50-3.98(5H,m),4.39-4.80(3H,m), 4.91(1H,quint,J=6.3 Hz), 7.53(2H,d,J=8.1 Hz),7.81(2H,d,J=8.4 Hz), 8.70(1H,brs), 10.25(1H,brs).

Example 106

[0663] Synthesis of3-{(2S,4S)-4-[N-(benzyloxycarbonylmethyl)-N-(4-cyanophenylmethyl)amino}-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0664] (1) Using the product (0.833 g) of Example 63 (1) and benzylbromoacetate (0.317 mL), and in the same manner as in Example 104 (1),3-{(2S,4S)-4-[N-(benzyloxycarbonylmethyl)-N-(4-cyanophenylmethyl)amino]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.992 g) was obtained as an oil.

[0665] (2) The above-mentioned compound (992 mg) was dissolved in ethylacetate (3.51 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.76 mL)was added thereto. The mixture was stirred at room temperature for 8 hrand the precipitated solid was collected by filtration to give the titlecompound (680 mg) as a white powder.

[0666]¹H-NMR(DMSO-d₆)δ1.67-1.85(1H,m), 2.53-2.71(1H,m), 2.94-3.20(3H,m),3.20-4.00(8H,m), 4.37-4.80(3H,m), 5.11(2H,s), 7.29-7.45(5H,m),7.50(2H,d,J=8.1 Hz), 7.78(2H,d,J=8.4 Hz), 8.75(1H,brs), 10.15(1H,brs).

Example 107

[0667] Synthesis of3-{(2S,4S)-4-[N-(carboxymethyl)-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine2 trifluoroacetate

[0668] (1) Using the product (0.833 g) of Example 63 (1) and tert-butylbromoacetate (0.443 mL), and in the same manner as in Example 104 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(tert-butoxycarbonylmethyl)-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.990 g) was obtained.

[0669] (2) The above-mentioned compound (881 mg) was dissolved in ethylacetate (3.06 mL) and 4 mol/L hydrochloric acid-ethyl acetate (6.91 mL)was added thereto. The mixture was stirred at room temperature for 3days. The precipitated solid was purified by HPLC to give the titlecompound (141 mg) as a white powder.

[0670]¹H-NMR(DMSO-d₆)δ1.65-1.84(1H,m), 2.57-2.74(1H,m), 2.96-3.19(3H,m),3.22-4.00(8H,m), 4.37-4.72(3H,m), 7.53(2H,d,J=8.4 Hz), 7.81(2H,d,J=8.1Hz), 8.77(1H,brs), 9.63(1H,brs).

Example 108

[0671] Synthesis of3-{(2S,4S)-4-[N-(4-carbamoylphenylmethyl)-N-(carboxymethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine2 trifluoroacetate

[0672] The title compound (41 mg) was obtained as a pale-yellow powderby purification of Example 107 (2) by HPLC.

[0673]¹H-NMR(DMSO-d₆)δ1.67-1.90(1H,m), 2.56-2.79(1H,m),2.90-4.20(11H,m), 4.36-4.74(3H,m), 7.34(1H,brs), 7.56(2H,d,J=8.1 Hz),7.84(2H,d,J=8.4 Hz), 7.96(1H,brs), 8.80(1H,brs), 9.60(1H,brs).

Example 109

[0674] Synthesis of3-{(2S,4S)-4-[N-(carbamoylmethyl)-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0675] (1) Using the product (0.833 g) of Example 63 (1) and2-bromoacetamide (0.276 mL), and in the same manner as in Example 104(1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(carbamoylmethyl)-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.599 g) was obtained.

[0676] (2) The above-mentioned compound (599 mg) was dissolved in ethylacetate (2.53 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.27 mL)was added thereto. The mixture was stirred at room temperature for 6 hrand the precipitated solid was collected by filtration to give the titlecompound (416 mg) as a white powder.

[0677]¹H-NMR(DMSO-d₆)δ1.76-1.99(1H,m), 2.62-2.83(1H,m),2.90-4.10(11H,m), 4.25-4.80(3H,m), 7.22(1H,brs), 7.44(1H,brs),7.64(2H,d,J=8.1 Hz), 7.84(2H,d,J=8.4 Hz), 8.82(1H,brs), 10.35(1H,brs).

Example 110

[0678] Synthesis of3-((2S,4S)-4-benzoylamino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine

[0679] (1) Using the title compound (499 mg) of Reference Example 10 andbenzoyl chloride (202 μL), and in the same manner as in ReferenceExample 7,3-((2S,4S)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(652 mg) was obtained as a white powder.

[0680] (2) Using the above-mentioned compound (648 mg), and in the samemanner as in Example 5 (2), the title compound (250 mg) was obtained asa white powder.

[0681]¹H-NMR(500 MHz,DMSO-d₆)δ1.76-1.81(1H,m), 2.33-2.39(1H,m),2.91-3.09(5H,m), 3.63-3.95(3H,m), 4.34-4.70(3H,m), 7.44-7.53(3H,m),7.80-7.82(2H,m), 8.38(1H,brs).

Example 111

[0682] Synthesis of3-[(2S,4S)-4-(4-cyanobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0683] (1) Using the title compound (543 mg) of Reference Example 10 and4-cyanobenzoyl chloride (313 mg), and in the same manner as in ReferenceExample 7,3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(804 mg) was obtained as a white powder.

[0684] (2) Using the above-mentioned compound (798 mg), and in the samemanner as in Example 5 (2), the title compound (513 mg) was obtained asa white powder.

[0685]¹H-NMR(500 MHz,DMSO-d₆)δ2.01-2.06(1H,m), 2.81-2.86(1H,m),3.03-3.14(2H,m), 3.36-3.50(2H,m), 3.65-3.94(2H,m), 4.45-4.75(4H,m),7.98-8.06(4H,m), 8.86(1H,brs), 9.07-9.12(1H,m), 10.49(1H,brs).

Example 112

[0686] Synthesis of3-[(2S,4S)-4-(5-chloro-2-nitrobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0687] (1) Using the title compound (495 mg) of Reference Example 10 and5-chloro-2-nitrobenzoic acid (300 mg), and in the same manner as inReference Example 9,3-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-chloro-2-nitrobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(340 mg) was obtained as a white powder.

[0688] (2) Using the above-mentioned compound (338 mg), and in the samemanner as in Example 5 (2), the title compound (272 mg) was obtained asa white powder.

[0689]¹H-NMR(DMSO-d₆)δ1.88-1.99(1H,m), 2.79-2.88(1H,m), 3.04-3.15(2H,m),3.26-3.36(1H,m), 3.47-3.94(3H,m), 4.44-4.75(4H,m), 7.80-7.84(2H,m),8.11-8.14(1H,m), 9.09-9.12(1H,m), 9.50(2H,brs).

Example 113

[0690] Synthesis of3-[(2S,4S)-4-(2,4-dichlorobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0691] (1) Using the title compound (440 mg) of Reference Example 10 and2,4-dichlorobenzoic acid (254 mg), and in the same manner as inReference Example 9,3-[(2S,4S)-1-tert-butoxycarbonyl-4-(2,4-dichlorobenzoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(356 mg) was obtained as a white powder.

[0692] (2) Using the above-mentioned compound (356 mg), and in the samemanner as in Example 5 (2), the title compound (211 mg) was obtained asa white powder.

[0693]¹H-NMR(DMSO-d₆)δ1.86-1.99(1H,m), 2.79-2.88(1H,m), 3.04-3.14(2H,m),3.26-3.31(1H,m), 3.47-3.95(3H,m), 4.43-4.75(4H,m), 7.50-7.56(2H,m),7.71(1H,s), 8.84-8.88(1H,m), 9.70(2H,brs).

Example 114

[0694] Synthesis of3-{(2S,4S)-4-[(3-nitrophenyl)acetyl]amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidinehydrochloride

[0695] (1) Using the title compound (370 mg) of Reference Example 10 and3-nitrophenylacetic acid (201 mg), and in the same manner as inReference Example 9,3-{(2S,4S)-1-tert-butoxycarbonyl-4-[(3-nitrophenyl)acetyl]amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(516 mg) was obtained as a white powder.

[0696] (2) Using the above-mentioned compound (515 mg), and in the samemanner as in Example 5 (2), the title compound (427 mg) was obtained asa white powder.

[0697]¹H-NMR(500 MHz,DMSO-d₆)δ1.86-1.93(1H,m), 2.74-2.78(1H,m),3.04-3.14(3H,m), 3.40-3.44(1H,m), 3.63(2H,s), 3.63-3.89(2H,m),4.36-4.70(4H,m), 7.60-7.63(1H,m), 7.72(1H,d,J=7.7 Hz), 8.12(1H,d,J=8.2Hz), 8.15(1H,s), 8.65-8.68(1H,m).

Example 115

[0698] Synthesis of3-[(2S,4S)-4-(trans-3-trifluoromethylcinnamoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0699] (1) Using the compound (338 mg) of Reference Example 10 and3-trifluoromethylcinnamoyl chloride (201 μL), and in the same manner asin Reference Example 7,3-[(2S,4S)-1-tert-butoxycarbonyl-4-(trans-3-trifluoromethylcinnamoyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(274 mg) was obtained as a white powder.

[0700] (2) Using the above-mentioned compound (270 mg), and in the samemanner as in Example 5 (2), the title compound (230 mg) was obtained asa white powder.

[0701]¹H-NMR(DMSO-d₆)δ1.78-1.88(1H,m), 2.79-2.87(1H,m), 3.04-3.22(3H,m),3.46-3.52(1H,m), 3.64-3.94(2H,m), 4.46-4.75(4H,m), 6.76(1H,d,J=15.9 Hz),7.57(1H,d,J=15.9 Hz), 7.64-7.76(2H,m), 7.89-8.03(2H,m), 8.70-8.75(1H,m),9.60(2H,.brs).

Example 116

[0702] Synthesis of3-{(2S,4S)-4-[N-(4-cyanobenzoyl)-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinehydrochloride

[0703] (1) The product (0.833 g) of Example 63 (1) was dissolved indichloromethane (10 mL), and triethylamine (0.418 mL) and 4-cyanobenzoylchloride (0.331 g) were added thereto. The mixture was stirred at roomtemperature for 18 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was dried and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanobenzoyl)-N-(4-cyanophenylmethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.956 g).

[0704] (2) The above-mentioned compound (514 mg) was dissolved in ethylacetate (1.88 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.18 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the precipitated solid was collected by filtration to give the titlecompound (320 g) as a white powder.

[0705]¹H-NMR(DMSO-d₆)δ1.62-2.39(1H,m), 2.45-2.82(1H,m), 2.90-3.25(2H,m),3.30-3.95(4H,m), 4.25-5.00(6H,m), 7.30-8.20(8H,m).

Example 117

[0706] Synthesis of3-{(2S,4S)-4-[N-acetyl-N-(5-cyano-2-pyridyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinehydrochloride

[0707] (1) Using the product (340 mg) of Example 58 (1) and acetylchloride (72 μL), and in the same manner as in Example 82 (1),3-{(2s,4S)-4-[N-acetyl-N-(5-cyano-2-pyridyl)amino]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(188 mg) was obtained.

[0708] (2) Using the above-mentioned compound (186 mg), and in the samemanner as in Example 82 (2), the title compound (121 mg) was obtained asa white powder.

[0709]¹H-NMR(500 MHz,DMSO-d₆)δ1.90-1.95(1H,m), 1.91(3H,s),2.75-2.80(1H,m), 3.03-3.11(2H,m), 3.40-3.44(1H,m), 3.50-3.54(1H,m),3.59-3.63(1H,m), 3.71-3.85(1H,m), 4.39-4.44(1H,m), 4.56-4.69(2H,m),5.04-5.08(1H,m), 7.75(1H,d,J=8.3 Hz), 8.50(1H,dd,J=8.3,2.1 Hz),9.01(1H,d,J=2.1 Hz).

Example 118

[0710] Synthesis of3-((2S,4S)-4-phthalimido-2-pyrrolidinylcarbonyl)-1,3-thiazolidinetrifluoroacetate

[0711] (1) The title compound (1.23 g) of Reference Example 10 wassuspended in toluene (20 mL), and phthalic anhydride (632 mg) andtriethylamine (60 μL) were added thereto. The mixture was refluxed for 5hr. To the reaction mixture was added 10% citric acid solution and themixture was extracted with ethyl acetate. The extract was washedsuccessively with saturated aqueous sodium hydrogencarbonate solutionand brine, and dried. The solvent was evaporated under reduced pressure.The residue was purified by silica gel chromatography to give3-((2S,4S)-1-tert-butoxycarbonyl-4-phthalimido-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(1.21 g) as a white solid.

[0712] (2) The above-mentioned compound (362 mg) was dissolved indichloromethane (4 mL) and trifluoroacetic acid (2 mL) was addedthereto. The mixture was stirred at room temperature for 20 hr. Thesolvent was evaporated under reduced pressure to give the title compound(374 mg) as a pale-yellow solid.

[0713]¹H-NMR(500 MHz,DMSO-d₆)δ2.38-2.44(1H,m), 2.80-2.84(1H,m),3.07-3.13(2H,m), 3.50-3.54(1H,m), 3.60-3.89(3H,m), 4.46-4.50(1H,m),4.62-4.78(2H,m), 4.97-5.00(1H,m), 7.86-7.90(4H,m), 8.74(1H,brs),9.90(1H,brs).

Example 119

[0714] Synthesis of3-[(2S,4S)-4-(4-nitrophthalimido)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrifluoroacetate

[0715] (1) Using the title compound (2.31 g) of Reference Example 10 and4-nitrophthalic anhydride (1.16 g), and in the same manner as in Example118 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-nitrophthalimido)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1.42 g) was obtained as a white solid.

[0716] (2) Using the above-mentioned compound (355 mg), and in the samemanner as in Example 118 (2), the title compound (298 mg) was obtainedas a white powder.

[0717]¹H-NMR(500 MHz,DMSO-d₆)δ2.40-2.45(1H,m), 2.82-2.88(1H,m),3.06-3.14(2H,m), 3.52-3.56(1H,m), 3.62-3.89(3H,m), 4.47-4.50(1H,m),4.62-4.78(2H,m), 5.01-5.07(1H,m), 8.15(1H,d,J=8.2 Hz), 8.51(1H,d,J=1.9Hz), 8.65(1H,dd,J=8.2,1.9 Hz), 9.24(2H,brs).

Example 120

[0718] Synthesis of3-[(2S,4S)-4-(3-phenylureido)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrifluoroacetate

[0719] (1) The title compound (401 mg) of Reference Example 10 wasdissolved in tetrahydrofuran (10 mL), and phenyl isocyanate (167 mg) wasadded thereto at room temperature. The mixture was stirred for 18 hr. Tothe reaction mixture was added 10% citric acid solution and the mixturewas extracted with ethyl acetate. The extract was washed successivelywith saturated aqueous sodium hydrogencarbonate solution and brine, anddried. The solvent was evaporated under reduced pressure to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-phenylureido)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(560 mg) as a white solid.

[0720] (2) The above-mentioned compound (532 mg) was dissolved intrifluoroacetic acid (2 mL) and the mixture was stirred at roomtemperature for 3 hr. The solvent was evaporated under reduced pressureto give the title compound (363 mg) as a brown powder.

[0721]¹H-NMR(500 MHz,DMSO-d₆)δ1.75-1.80(1H,m), 2.75-2.80(1H,m),3.04-3.20(3H,m), 3.43-3.47(1H,m), 3.68-3.89(2H,m), 4.40-4.71(4H,m),6.72-6.75(1H,m), 6.91(1H,t,J=7.4 Hz), 7.21-7.24(2H,m), 7.39(2H,d,J=7.8Hz), 8.85(1H,brs), 8.89-8.90(1H,m), 9.60(1H,brs).

Example 121

[0722] Synthesis of3-{(2S,4S)-4-[3-(4-cyanophenyl)ureido]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[0723] (1) Using the title compound (640 mg) of Reference Example 10 and4-cyanophenyl isocyanate (321 mg), and in the same manner as in Example120 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[3-(4-cyanophenyl)ureido]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(992 mg) was obtained as a white powder.

[0724] (2) The above-mentioned compound (978 mg) was dissolved inchloroform (5 mL), and then dissolved in trifluoroacetic acid (3 mL),and the mixture was stirred at room temperature for 8 hr. The solventwas evaporated under reduced pressure and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with chloroform. The extract was concentrated under reducedpressure to give the title compound (140 mg) as a white powder.

[0725]¹H-NMR(DMSO-d₆)δ1.60-1.68(1H,m), 2.22-2.32(1H,m), 2.67-2.72(1H,m),2.91-3.11(4H,m), 3.65-3.93(3H,m), 4.13-4.16(1H,m), 4.43-4.72(2H,m),6.47(1H,d,J=7.2 Hz), 7.56(2H,d,J=8.7 Hz), 7.65(2H,d,J=8.7 Hz),9.11(1H,s).

Example 122

[0726] Synthesis of3-((2S,4S)-4-phenylsulfonylamino-2-pyrrolidinylcarbonyl)-1,3-thiazolidinehydrochloride

[0727] (1) The title compound (543 mg) of Reference Example 10 wasdissolved in dichloromethane (10 mL), and 4-methylmorpholine (240 μL)and benzenesulfonyl chloride (240 μL) were added thereto at roomtemperature. The mixture was stirred for 17 hr. To the reaction mixturewas added 10% citric acid solution, and the mixture was extracted withethyl acetate. The extract was washed successively with saturatedaqueous sodium hydrogencarbonate solution and brine, and dried. Thesolvent was evaporated under reduced pressure to give3-((2S,4S)-1-tert-butoxycarbonyl-4-phenylsulfonylamino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(644 mg) as a white powder.

[0728] (2) The above-mentioned compound (634 mg) was dissolved in ethylacetate (4 mL) and 4 mol/L hydrochloric acid-ethyl acetate (1.8 mL) wasadded thereto. The mixture was stirred at room temperature for 67 hr.The precipitate was collected by filtration to give the title compound(437 mg) as a pale-yellow powder.

[0729]¹H-NMR(500 MHz,DMSO-d₆)δ1.68-1.74(1H,m), 2.50-2.58(1H,m),3.00-3.08(3H,m), 3.17-3.20(1H,m), 3.53-3.87(3H,m), 4.38-4.63(3H,m),7.62-7.71(3H,m), 7.84-7.85(2H,m), 8.24-8.27(1H,m), 9.50(2H,brs).

Example 123

[0730] Synthesis of3-[(2S,4S)-4-(4-cyanophenylsulfonyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidinehydrochloride

[0731] (1) Using the title compound (1.09 g) of Reference Example 10 and4-cyanobenzenesulfonyl chloride (0.780 g), and in the same manner as inExample 122 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-cyanophenylsulfonyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1.67 g) was obtained as a white powder.

[0732] (2) Using the above-mentioned compound (798 mg), and in the samemanner as in Example 122 (2), the title compound (544 mg) was obtainedas a pale-yellow powder.

[0733]¹H-NMR(500 MHz,DMSO-d₆)δ1.68-1.75(1H,m), 2.53-2.59(1H,m),3.02-3.09(3H,m), 3.23-3.28(1H,m), 3.54-3.90(3H,m), 4.40-4.64(3H,m),8.01(2H,d,J=8.4 Hz), 8.13(2H,d,J=8.4 Hz), 8.62-8.65(1H,m), 9.93(2H,brs).

Example 124

[0734] Synthesis of3-{(2S,4S)-4-[N-(4-cyanophenylmethyl)-N-(4-cyanophenylsulfonyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinehydrochloride

[0735] (1)3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylsulfonyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine[product of Example 123 (1), 856 mg] was dissolved in DMF (20 mL), andpotassium carbonate (380 mg) and 4-cyanobenzyl bromide (400 mg) wereadded thereto at room temperature. The mixture was stirred for 4 hr. Tothe reaction mixture was added 10% citric acid solution, and theprecipitate was collected by filtration to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(4-cyanophenylsulfonyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(900 mg) as a pale-yellow solid.

[0736] (2) Using the above-mentioned compound (900 mg), and in the samemanner as in Example 122 (2), the title compound (800 mg) was obtainedas a pale-yellow powder.

[0737]¹H-NMR(500 MHz,DMSO-d₆)δ1.54-1.60(1H,m), 2.45-2.50(1H,m),2.79(1H,dd,J=8.7,1.6 Hz), 3.00-3.20(3H,m), 3.55-3.58(1H,m),3.68-3.82(1H,m), 4.34-4.63(3H,m), 4.65(2H,s), 4.87-4.93(1H,m),7.51(2H,d,J=8.2 Hz), 7.86(2H,d,J=8.2 Hz), 8.11(2H,d,J=8.4 Hz),8.16(2H,d,J=8.4 Hz), 8.85(1H,brs), 9.91(1H,brs).

Example 125

[0738] Synthesis of3-[(2S,4S)-4-(1-pyrrolidinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0739] (1) Using the title compound (1.00 g) of Reference Example 12 andpyrrolidine (0.274 g), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-pyrrolidinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(0.793 g) was obtained as a white solid.

[0740] (2) Using the above-mentioned compound (791 mg), and in the samemanner as in Example 70 (2), the title compound (626 mg) was obtained asa white powder.

[0741]¹H-NMR(DMSO-d₆)δ1.80-2.15(6H,m), 2.16-2.28(2H,m), 2.95-3.25(3H,m),3.50-3.95(3H,m), 4.02-4.15(2H,m), 4.45-4.75(4H,m).

Example 126

[0742] Synthesis of3-((2S,4S)-4-morpholino-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[0743] (1) Using the title compound (1.00 g) of Reference Example 12 andmorpholine (0.319 g), and in the same manner as in Example 70 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-morpholino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(0.987 g) was obtained as a white solid.

[0744] (2) Using the above-mentioned compound (985 mg), and in the samemanner as in Example 70 (2), the title compound (746 mg) was obtained asa white powder.

[0745]¹H-NMR(DMSO-d₆)δ2.22-2.35(2H,m), 2.90-3.50(7H,m), 3.70-4.20(5H,m),4.46-4.83(6H,m), 9.30(1H,brs).

Example 127

[0746] Synthesis of3-((2S,4S)-4-piperidino-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[0747] (1) Using the title compound (1.00 g) of Reference Example 12 andpiperidine (0.318 g), and in the same manner as in Example 70 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-piperidino-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(0.908 g) was obtained as a white solid.

[0748] (2) Using the above-mentioned compound (906 mg), and in the samemanner as in Example 70 (2), the title compound (705 mg) was obtained asa white powder.

[0749]¹H-NMR(DMSO-d₆)δ1.65-1.90(6H,m), 2.18-2.34(2H,m), 2.85-3.20(4H,m),3.30-3.50(2H,m), 3.55-4.05(2H,m), 4.50-4.82(6H,m).

Example 128

[0750] Synthesis of3-[(2S,4S)-4-(4-hydroxypiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrihydrochloride

[0751] (1) Using the title compound (988 mg) of Reference Example 12 and4-hydroxypiperidine (867 mg), and in the same manner as in Example 70(1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-hydroxypiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(408 mg) was obtained as a white solid.

[0752] (2) Using the above-mentioned compound (408 mg), and in the samemanner as in Example 70 (2), the title compound (250 mg) was obtained asa white powder.

[0753]¹H-NMR(DMSO-d₆)δ1.60-1.82(2H,m),δ1.84-2.05(2H,m), 2.12-2.33(2H,m),2.85-3.55(6H,m), 3.59-4.10(6H,m), 4.45-4.78(3H,m).

Example 129

[0754] Synthesis of3-[(2S,4S)-4-(3-azaspiro[5.5]undec-3-yl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine2 trifluoroacetate

[0755] (1) The title compound (340 mg) of Reference Example 12,3-azaspiro[5.5]undecene (210 mg) and acetic acid (0.066 mL) weredissolved in 1,2-dichloroethane (10 mL), and sodiumtriacetoxyborohydride (485 mg) was added thereto. The mixture wasstirred at room temperature for 17 hr. The reaction mixture was added toand the mixture was extracted with chloroform. The extract was washedwith brine and dried. The solvent was evaporated under reduced pressure.Ethyl acetate was added to the residue, and the precipitate wascollected by filtration to give3-[(2S,4S)-4-(3-azaspiro[5.5]undec-3-yl)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(141 mg) as a white solid.

[0756] (2) The above-mentioned compound (140 mg) was dissolved inmethanol (3 mL) and chloroform (3 mL) and 4 mol/L hydrochloricacid-1,4-dioxane (1 mL) were added thereto. The mixture was stirred atroom temperature for 18 hr. The solvent was evaporated under reducedpressure and the residue was purified by HPLC to give the title compound(52 mg) as a white solid.

[0757]¹H-NMR(500 MHz,DMSO-d₆)δ1.39-1.75(14H,m), 2.08-2.14(1H,m),2.96-3.30(8H,m), 3.64-3.89(3H,m), 4.05-4.10(1H,m), 4.44-4.69(3H,m),9.84(2H,brs).

Example 130

[0758] Synthesis of3-[(2S,4S)-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0759] (1) Using the title compound (1.00 g) of Reference Example 12 and4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane (0.81 g), and in the samemanner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1.64 g) was obtained as a white solid powder.

[0760] (2) Using the above-mentioned compound (1.64 g), and in the samemanner as in Example 70 (2), the title compound (0.900 g) was obtainedas a white powder.

[0761]¹H-NMR(DMSO-d₆)δ1.50-2.16(6H,m), 2.80-3.30(5H,m), 3.40-3.95(6H,m),4.45-4.80(5H,m), 6.75-6.85(1H,m), 6.90-7.05(2H,m), 7.21-7.30(2H,m).

Example 131

[0762] Synthesis of3-[(2S,4S)-4-(4-phenyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0763] (1) Using the title compound (461 mg) of Reference Example 12 and4-phenylpiperidine (300 mg), and in the same manner as in Example 129(1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-phenylpiperidi)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(118 mg) was obtained as a white solid.

[0764] (2) Using the above-mentioned compound (116 mg), and in the samemanner as in Example 129 (2), the title compound (78 mg) was obtained asa white powder.

[0765]¹H-NMR(DMSO-d₆)δ1.98-2.06(4H,m), 2.22-2.33(1H,m), 2.84-2.90(1H,m),3.00-3.20(5H,m), 3.53-4.04(7H,m), 4.47-4.74(3H,m), 7.23-7.38(5H,m).

Example 132

[0766] Synthesis of3-[(2S,4S)-4-(1,2,3,6-tetrahydro-4-phenyl-1-pyridyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[0767] (1) Using the title compound (236 mg) of Reference Example 12 and1,2,3,6-tetrahydro-4-phenyl-1-pyridine (150 mg), and in the same manneras in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1,2,3,6-tetrahydro-4-phenyl-1-pyridyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(227 mg) was obtained as a white solid.

[0768] (2) The above-mentioned compound (225 mg) was dissolved indichloromethane (4 mL), and trifluoroacetic acid (1 mL) was addedthereto at room temperature. The mixture was stirred for 16 hr. Thesolvent was evaporated under reduced pressure, and saturated aqueoussodium hydrogencarbonate solution was added to the residue. The mixturewas extracted with chloroform. The extract was washed with brine anddried. The solvent was evaporated under reduced pressure. The residuewas dissolved in ethyl acetate and 4 mol/L hydrochloric acid-ethylacetate was added and the precipitate was collected by filtration togive the title compound (158 mg) as a white powder.

[0769]¹H-NMR(500 MHz,DMSO-d₆)δ2.27-2.32(1H,m), 2.83(2H,brs),3.03-3.16(4H,m), 3.68-4.15(8H,m), 4.48-4.75(3H,m), 6.19(1H,s),7.32-7.41(3H,m), 7.49-7.51(2H,m).

Example 133

[0770] Synthesis of3-{(2S,4S)-4-[4-(p-tolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0771] (1) The title compound (504 mg) of Reference Example 12,4-(p-tolyl)piperidine (353 mg) and acetic acid (0.096 mL) were dissolvedin 1,2-dichloroethane (10 mL), and sodium triacetoxyborohydride (710 mg)was added thereto. The mixture was stirred at room temperature for 18hr. The reaction mixture was added to water and the mixture wasextracted with chloroform. The extract was washed with brine and dried.The solvent was evaporated under reduced pressure to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(p-tolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(115 mg) as a white solid.

[0772] (2) The above-mentioned compound (114 mg) was dissolved inmethanol (3 mL), and chloroform (3 mL) and 4 mol/L hydrochloricacid-1,4-dioxane (1 mL) were added thereto. The mixture was stirred atroom temperature for 18 hr. The solvent was evaporated under reducedpressure to give the title compound (84 mg) as a white powder.

[0773]¹H-NMR(DMSO-d₆)δ1.97-2.06(4H,m), 2.25-2.35(1H,m), 2.27(3H,s),2.78-2.85(1H,m), 3.00-3.17(5H,m), 3.50-4.05(7H,m), 4.47-4.74(3H,m),7.10-7.17(4H,m).

Example 134

[0774] Synthesis of3-{(2S,4S)-4-[4-(3,4-xylyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0775] (1) Using the title compound (450 mg) of Reference Example 12 and4-(3,4-xylyl)piperidine (312 mg), and in the same manner as in Example70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-xylyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine618 mg) was obtained as a white solid.

[0776] (2) Using the above-mentioned compound (613 mg), and in the samemanner as in Example 70 (2), the title compound (374 mg) was obtained asa white powder.

[0777]¹H-NMR(DMSO-d₆)δ1.86-2.15(4H,m), 2.18(3H,s), 2.20(3H,s),2.22-2.37(1H,m), 2.68-2.74(1H,m), 2.93-3.25(5H,m), 3.42-4.07(7H,m),4.44-4.77(3H,m), 6.88-7.04(2H,m), 7.09(1H,d,J=7.8 Hz), 10.1(1H,brs),11.91(1H,brs).

Example 135

[0778] Synthesis of3-{(2S,4S)-4-[4-(2,4-dimethoxyphenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0779] (1) Using the title compound (487 mg) of Reference Example 12 and4-(2,4-dimethoxyphenyl)piperidine (430 mg), and in the same manner as inExample 133 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2,4-dimethoxyphenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(82 mg) was obtained as a pale-brown solid.

[0780] (2) Using the above-mentioned compound (82 mg), and in the samemanner as in Example 133 (2), the title compound (61 mg) was obtained asa brown powder.

[0781]¹H-NMR(DMSO-d₆)δ1.99-2.08(4H,m), 2.25-2.35(1H,m), 2.78-3.17(6H,m),3.53-4.06(7H,m), 3.72(3H,s), 3.75(3H,s), 4.47-4.75(3H,m),6.74(1H,d,J=8.1 Hz), 6.83(1H,s), 6.91(1H,d,J=8.1 Hz).

Example 136

[0782] Synthesis of3-{(2S,4S)-4-[4-(2,3-dihydrobenzo[b]furan-5-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0783] (1) Using the title compound (450 mg) of Reference Example 12 and4-(2,3-dihydrobenzo[b]furan-5-yl)piperidine (335 mg), and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2,3-dihydrobenzo[b]furan-5-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(494 mg) was obtained as a white solid.

[0784] (2) Using the above-mentioned compound (489 mg), and in the samemanner as in Example 70 (2), the title compound (330 mg) was obtainedas-a white powder.

[0785]¹H-NMR(DMSO-d₆)δ1.84-2.14(4H,m), 2.21-2.37(1H,m), 2.72-2.86(1H,m),2.96-3.26(7H,m), 3.47-4.07(7H,m), 4.44-4.77(5H,m), 6.71(1H,d,J=8.1 Hz),6.94(1H,d,J=8.1 Hz), 7.09(1H,s), 9.9(1H,brs), 11.89(1H,brs).

Example 137

[0786] Synthesis of3-{(2S,4S)-4-[4-(3,4-methylenedioxyphenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0787] (1) Using the title compound (505 mg) of Reference Example 12 and4-(3,4-methylenedioxyphenyl)piperidine (414 mg), and in the same manneras in Example 133 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-methylenedioxyphenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(105 mg) was obtained as a white solid.

[0788] (2) Using the above-mentioned compound (105 mg), and in the samemanner as in Example 133 (2), the title compound (61 mg) was obtained asa white powder.

[0789]¹H-NMR(DMSO-d₆)δ1.97-2.04(4H,m), 2.25-2.35(1H,m), 2.78-2.82(1H,m),3.00-3.17(5H,m), 3.50-4.03(7H,m), 4.47-4.76(3H,m), 5.98(2H,s),6.70(1H,d,J=8.1 Hz), 6.82(1H,s), 6.87(1H,d,J=8.1 Hz).

Example 138

[0790] Synthesis of3-{(2S,4S)-4-[4-(4-fluoro-3-methylphenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0791] (1) Using the title compound (450 mg) of Reference Example 12 and4-(4-fluoro-3-methylphenyl)piperidine (326 mg), and in the same manneras in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-fluoro-3-methylphenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(603 mg) was obtained as a white solid.

[0792] (2) Using the above-mentioned compound (597 mg), and in the samemanner as in Example 70 (2), the title compound (441 mg) was obtained asa white powder.

[0793]¹H-NMR(DMSO-d₆)δ1.90-2.16(4H,m), 2.23(3H,s), 2.25-2.38(1H,m),2.77-2.92(1H,m), 2.96-3.26(5H,m), 3.48-4.07(7H,m), 4.46-4.78(3H,m),7.04-7.19(3H,m), 10.5(1H,brs), 11.94(1H,brs).

Example 139

[0794] Synthesis of3-{(2S,4S)-4-[4-(3,4-dichlorophenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0795] (1) Using the title compound (480 mg) of Reference Example 12 and4-(3,4-dichlorophenyl)piperidine (442 mg), and in the same manner as inExample 133 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-dichlorophenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(820 mg) was obtained as a white powder.

[0796] (2) Using the above-mentioned compound (820 mg), and in the samemanner as in Example 133 (2), the title compound (654 mg) was obtainedas a white powder.

[0797]¹H-NMR(DMSO-d₆)δ1.99-2.10(4H,m), 2.25-2.35(1H,m), 2.89-3.20(6H,m),3.53-4.06(7H,m), 4.47-4.77(3H,m), 7.26(1H,d,J=8.1 Hz), 7.50(1H,d,J=3.3Hz), 7.61(1H,dd,J=8.1,3.3 Hz).

Example 140

[0798] Synthesis of3-{(2S,4S)-4-[4-(4-chloro-3-trifluoromethylphenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0799] (1) Using the title compound (503 mg) of Reference Example 12 and4-(4-chloro-3-trifluoromethylphenyl)piperidine (530 mg), and in the samemanner as in Example 133 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chloro-3-trifluoromethylphenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(189 mg) was obtained as a white solid.

[0800] (2) Using the above-mentioned compound (189 mg), and in the samemanner as in Example 133 (2), the title compound (116 mg) was obtainedas a white powder.

[0801]¹H-NMR(DMSO-d₆)δ2.07-2.12(4H,m), 2.25-2.35(1H,m), 3.00-3.17(6H,m),3.59-4.10(7H,m), 4.47-4.76(3H,m), 7.57-7.74(3H,m).

Example 141

[0802] Synthesis of3-{(2S,4S)-4-[4-(1-naphthyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0803] (1) Using the title compound (601 mg) of Reference Example 12 and4-(1-naphthyl)piperidine (630 mg), and in the same manner as in Example133 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-naphthyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(130 mg) as a pale-brown solid.

[0804] (2) Using the above-mentioned compound (129 mg), and in the samemanner as in Example 133 (2), the title compound (72 mg) was obtained asa brown powder.

[0805]¹H-NMR(500 MHz,DMSO-d₆)δ1.99-2.35(5H,m), 3.05-3.41(5H,m),3.63-4.06(8H,m), 4.49-4.75(3H,m), 7.38-7.39(1H,m), 7.45-7.61(3H,m),7.83-7.84(1H,m), 7.95-7.97(1H,m), 8.21-8.23(1H,m).

Example 142

[0806] Synthesis of3-{(2S,4S)-4-[4-(2-naphthyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0807] (1) Using the title compound (450 mg) of Reference Example 12 and4-(2-naphthyl)piperidine (349 mg), and in the same manner as in Example70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-naphthyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(721 mg) was obtained as a white solid.

[0808] (2) Using the above-mentioned compound (616 mg), and in the samemanner as in Example 70 (2), the title compound (206 mg) was obtained asa white powder.

[0809]¹H-NMR(DMSO-d₆)δ2.03-2.40(5H,m), 2.97-3.35(6H,m), 3.54-4.15(7H,m),4.47-4.80(3H,m), 7.40-7.57(3H,m), 7.73(1H,s), 7.86-7.97(3H,m),10.1(1H,brs), 11.95(1H,brs).

Example 143

[0810] Synthesis of3-{(2S,4S)-4-[4-(2-benzo[b]thienyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0811] (1) Using the title compound (450 mg) of Reference Example 12 and4-(2-benzo[b]thienyl)piperidine (330 mg), and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-benzo[b]thienyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(531 mg) was obtained as a white solid.

[0812] (2) Using the above-mentioned compound (447 mg), and in the samemanner as in Example 70 (2), the title compound (258 mg) was obtained asa white powder.

[0813]¹H-NMR(DMSO-d₆)δ2.03-2.40(5H,m), 2.96-4.10(13H,m),4.46-4.77(3H,m), 7.23-7.42(3H,m), 7.78(1H,d,J=7.2 Hz), 7.92(1H,d,J=7.5Hz), 10.3(1H,brs), 11.95(1H,brs).

Example 144

[0814] Synthesis of3-{(2S,4S)-4-[4-(1-indolinyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0815] (1) 1-tert-Butoxycarbonylpiperidin-4-one (2.50 g), indoline (1.50g) and acetic acid (0.73 mL) were dissolved in 1,2-dichloroethane (75mL), and sodium triacetoxyborohydride (5.32 g) was added thereto. Themixture was stirred at room temperature for 12 hr. The reaction mixturewas added to iced water and the mixture was extracted with chloroform.The extract was dried and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography to give1-tert-butoxycarbonyl-4-(1-indolinyl)piperidine (2.82 g).

[0816] (2) The above-mentioned compound (2.82 g) was dissolved inmethanol (20 mL) and 4 mol/L hydrochloric acid-1,4-dioxane (20 mL) wasadded thereto. The mixture was stirred at room temperature for 12 hr.The reaction mixture was added to aqueous sodium hydrogencarbonatesolution, and the mixture was extracted with chloroform. The extract wasdried and the solvent was evaporated under reduced pressure to give4-(1-indolinyl)piperidine (0.60 g).

[0817] (3) Using the above-mentioned compound (470 mg) and the titlecompound (700 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-indolinyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(449 mg) was obtained as a white solid.

[0818] (4) Using the above-mentioned compound (448 mg), and in the samemanner as in Example 70 (2), the title compound (350 mg) was obtained asa white powder.

[0819]¹H-NMR(DMSO-d₆)δ1.85-2.30(5H,m), 2.85-3.25(9H,m), 3.50-4.02(8H,m),4.52-4.81(3H,m), 6.51-6.60(2H,m), 6.98-7.05(2H,m).

Example 145

[0820] Synthesis of3-{(2S,4S)-4-[4-(1-indolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0821] (1) Using the title compound (604 mg) of Reference Example 12 and4-(1-indolyl)piperidine (403 mg), and in the same manner as in Example70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-indolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(868 mg) was obtained as a white solid.

[0822] (2) Using the above-mentioned compound (868 mg), and in the samemanner as in Example 70 (2), the title compound (642 mg) was obtained asa white powder.

[0823]¹H-NMR(DMSO-d₆)δ2.05-2.60(6H,m), 2.99-3.18(4H,m), 3.55-4.20(6H,m),4.30-4.90(5H,m), 6.50(1H,d,J=3.0 Hz), 7.05(1H, dd,J=8.2,3.0 Hz),7.16(1H,dd,J=8.1,3.0 Hz), 7.35(1H,d,J=3.0 Hz), 7.57(1H,d,J=8.1 Hz),7.61(1H,d,J=8.1 Hz), 9.30(1H,brs), 10.00(1H,brs).

Example 146

[0824] Synthesis of3-{(2S,4S)-4-[4-(5-bromo-1-indolinyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0825] (1) Using 1-tert-butoxycarbonylpiperidin-4-one (2.81 g) and5-bromo-1-indoline (3.00 g), and in the same manner as in Example 144(1), 1-tert-butoxycarbonyl-4-(5-bromo-1-indolinyl)piperidine (3.34 g)was obtained.

[0826] (2) Using the above-mentioned compound (3.34 g), and in the samemanner as in Example 144 (2), 4-(5-bromo-1-indolinyl)piperidine (1.79 g)was obtained.

[0827] (3) Using the above-mentioned compound (1.12 g) and the titlecompound (1.20 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(5-bromo-1-indolinyl)piperidino]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.27 g) was obtained as a white powder.

[0828] (4) Using the above-mentioned compound (1.27 g), and in the samemanner as in Example 70 (2), the title compound (0.850 g) was obtainedas a white powder.

[0829]¹H-NMR(DMSO-d₆)δ1.76-1.98(2H,m), 2.01-2.20(2H,m), 2.21-2.35(2H,m),2.85-3.30(9H,m), 3.11-3.45(2H,m), 3.55-4.10(5H,m), 4.55-4.85(3H,m),6.49(1H,d,J=8.4 Hz), 7.13(1H,d,J=1.8 Hz), 7.15(1H,dd,J=8.4,1.8 Hz),9.25(1H,brs).

Example 147

[0830] Synthesis of3-{(2S,4S)-4-[4-(2-oxo-1-benzimidazolinyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0831] (1) Using the title compound (450 mg) of Reference Example 12 and4-(2-oxo-1-benzimidazolinyl)piperidine (358 mg), and in the same manneras in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-oxo-1-benzimidazolinyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(752 mg) was obtained as a white solid.

[0832] (2) The above-mentioned compound (635 mg) was dissolved in 1.5mol/L hydrochloric acid-methanol (5 mL), and the mixture was stirred atroom temperature for 36 hr. The reaction mixture was concentrated underreduced pressure and ethanol (10 mL) was added to the residue. Theprecipitate was collected by filtration to give the title compound (352mg) as a pale-brown powder.

[0833]¹H-NMR(DMSO-d₆)δ1.83-1.98(2H,m), 2.20-2.37(1H,m), 2.72-2.93(2H,m),2.96-3.45(5H,m), 3.52-4.10(7H,m), 4.46-4.77(4H,m), 7.00(3H,brs),7.58(1H,brs), 10.97(1H,brs), 12.23(1H,brs).

Example 148

[0834] Synthesis of3-[(2S,4S)-4-(4-anilinopiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrihydrochloride

[0835] (1) Using 1-tert-butoxycarbonylpiperidin-4-one (2.50 g) andaniline (1.24 g), and in the same manner as in Example 144 (1),4-anilino-1-tert-butoxycarbonylpiperidine (2.35 g) was obtained.

[0836] (2) Using the above-mentioned compound (2.34 g), and in the samemanner as in Example 144 (2), 4-anilinopiperidine (0.88 g) as obtained.

[0837] (3) Using the above-mentioned compound (320 mg) and the titlecompound (500 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-[(2S,4S)-4-(4-anilinopiperidino)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(679 mg) was obtained as a white solid.

[0838] (4) Using the above-mentioned compound (678 mg), and in the samemanner as in Example 70 (2), the title compound (469 mg) was obtained asa white powder.

[0839]¹H-NMR(DMSO-d₆)δ1.98-2.45(6H,m), 2.90-3.25(6H,m), 3.30-4.25(5H,m),4.50-4.85(4H,m), 6.95-7.50(5H,m), 9.22(1H,brs).

Example 149

[0840] Synthesis of3-{(2S,4S)-4-[4-(4-nitrophenyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0841] (1) 4-Amino-1-tert-butoxycarbonylpiperazine (3.00 g),4-fluoronitrobenzene (2.54 g) and N,N-diisopropylethylamine (8.82 g)were dissolved in N-methyl-2-pyrrolidone (30 mL), and the mixture wasstirred at 80° C. for 18 hr. The reaction mixture was added to water andthe mixture was extracted with ethyl acetate. The extract was washedwith brine and dried. The solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography to give1-tert-butoxycarbonyl-4-(4-nitrophenyl)aminopiperidine (2.55 g) as awhite solid.

[0842] (2) Using the above-mentioned compound (1.00 g), and in the samemanner as in Example 144 (2), 4-(4-nitrophenyl)aminopiperidine (0.563 g)was obtained.

[0843] (3) Using the above-mentioned compound (562 mg) and the titlecompound (761 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitrophenyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(780 mg) was obtained as a yellow solid.

[0844] (4) Using the above-mentioned compound (778 mg), and in the samemanner as in Example 70 (2), the title compound (575 mg) was obtained asa yellow powder.

[0845]¹H-NMR(DMSO-d₆)δ1.85-2.01(2H,m), 2.05-2.24(2H,m), 2.25-2.45(2H,m),3.00-3.21(5H,m), 3.50-4.20(7H,m), 4.48-4.85(3H,m), 6.72(2H,d,J=9.3 Hz),8.00(2H,d,J=9.3 Hz), 9.21(1H,brs).

Example 150

[0846] Synthesis of3-{(2S,4S)-4-[4-(4-trifluoromethylphenyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0847] (1) Using 1-tert-butoxycarbonylpiperidin-4-one (2.50 g) and4-trifluoromethylaniline (2.12 g), and in the same manner as in Example144 (1),1-tert-butoxycarbonyl-4-(4-trifluoromethylphenyl)aminopiperidine (2.23g) was obtained.

[0848] (2) Using the above-mentioned compound (2.23 g), and in the samemanner as in Example 144 (2), 4-(4-trifluoromethylphenyl)aminopiperidine(1.36 g) was obtained.

[0849] (3) Using the above-mentioned compound (447 mg) and the titlecompound (500 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-trifluoromethylphenyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(775 mg) was obtained as a white solid.

[0850] (4) Using the above-mentioned compound (774 mg), and in the samemanner as in Example 70 (2), the title compound (514 mg) was obtained asa white powder.

[0851]¹H-NMR(DMSO-d₆)δ1.75-1.95(2H,m), 2.05-2.30(2H,m), 2.25-2.55(2H,m),2.95-3.30(6H,m), 3.40-4.15(5H,m), 4.50-4.80(4H,m), 6.72(2H,d,J=8.7 Hz),7.38(2H,d,J=8.7 Hz), 9.21(1H,brs).

Example 151

[0852] Synthesis of3-{(2S,4S)-4-[4-(4-chlorophenyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0853] (1) Using 1-tert-butoxycarbonylpiperidin-4-one (3.00 g) and4-chloroaniline (1.92 g), and in the same manner as in Example 144 (1),1-tert-butoxycarbonyl-4-(4-chlorophenyl)aminopiperidine (2.77 g) wasobtained.

[0854] (2) Using the above-mentioned compound (2.76 g), and in the samemanner as in Example 144 (2), 4-(4-chlorophenyl)aminopiperidine (1.07 g)was obtained.

[0855] (3) Using the above-mentioned compound (725 mg) and the titlecompound (500 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chlorophenyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(553 mg) was obtained as an oil.

[0856] (4) Using the above-mentioned compound (550 mg), and in the samemanner as in Example 70 (2), the title compound (416 mg) was obtained asa white powder.

[0857]¹H-NMR(DMSO-d₆)δ1.65-1.99(2H,m), 2.05-2.35(3H,m), 2.95-3.25(5H,m),3.26-4.15(8H,m), 4.48-4.82(3H,m), 6.58-6.85(2H,m), 7.08-7.20(2H,m),9.22(1H,brs).

Example 152

[0858] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-pyridyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0859] (1) Using the title compound (254 mg) of Reference Example 12 and4-(5-cyano-2-pyridyl)aminopiperidine (155 mg), and in the same manner asin Example 70 (1),3-{(2$,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)aminopiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(225 mg) was obtained as a white solid.

[0860] (2) Using the above-mentioned compound (224 mg), and in the samemanner as in Example 70 (2), the title compound (219 mg) was obtained asa white powder.

[0861]¹H-NMR(DMSO-d₆)δ1.80-1.99(2H,m), 2.02-2.20(2H,m), 2.21-2.45(2H,m),2.98-3.23(5H,m), 3.75-4.20(7H,m), 4.55-4.86(3H,m), 6.55-6.62(1H,m),7.72(1H,d,J=9.0 Hz), 8.42(1H,s), 9.22(1H,brs).

Example 153

[0862] Synthesis of3-{(2S,4S)-4-[4-(N-methylanilino)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0863] (1)3-[(2S,4S)-4-(4-Anilinopiperidino)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine[product of Example 148 (3), 1.18 g] was dissolved in 1,2-dichloroethane(75 mL), and sodium triacetoxyborohydride (5.32 g), acetic acid (0.73mL) and 37% formaldehyde solution (5.0 mL) were added thereto. Themixture was stirred at room temperature for 12 hr. The reaction mixturewas added to water, and the mixture was extracted with chloroform. Theextract was dried and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(N-methylanilino)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolinine(967 mg).

[0864] (2) Using the above-mentioned compound (965 mg), and in the samemanner as in Example 70 (2), the title compound (618 mg) was obtained asa white powder.

[0865]¹H-NMR(DMSO-d₆)δ1.75-2.35(6H,m), 2.78-3.28(9H,m), 3.40-4.15(6H,m),4.48-4.85(3H,m), 7.20-7.75(5H,m), 9.22(1H,brs), 9.22(1H,brs).

Example 154

[0866] Synthesis of3-{(2S,4S)-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine2 trifluoroacetate

[0867] (1) The title compound (593 mg) of Reference Example 12 wasdissolved in methanol (10 mL), and4-(4-chlorophenyl)-4-hydroxypiperidine (500 mg), acetic acid (113 μL)and sodium cyanoborohydride (124 mg) were added thereto at roomtemperature. The mixture was stirred for 21 hr. Water was added to thereaction mixture, and the mixture was extracted with chloroform. Theextract was washed with brine and dried. The solvent was evaporatedunder reduced pressure to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(428 mg) as a white solid.

[0868] (2) Formic acid (10 mL) was added to the above-mentioned compound(427 mg). The mixture was stirred at room temperature for 21 hr. Thesolvent was evaporated under reduced pressure and the residue waspurified by HPLC to give the title compound (78 mg) as a white powder.

[0869]¹H-NMR(DMSO-d₆)δ1.81-1.85(2H,m), 2.05-2.19(3H,m),3.00-4.06(12H,m), 4.45-4.71(3H,m), 5.60(1H,brs), 7.42-7.50(4H,m).

Example 155

[0870] Synthesis of3-{(2S,4S)-4-[4-ethoxycarbonyl-4-(4-fluorophenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0871] (1) Using the title compound (450 mg) of Reference Example 12 and4-ethoxycarbonyl-4-(4-fluorophenyl)piperidine (414 mg), and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-ethoxycarbonyl-4-(4-fluorophenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(742 mg) was obtained as a white solid.

[0872] (2) The above-mentioned compound (321 mg) was dissolved inethanol (4 mL), and 4.6 mol/L hydrochloric acid-ethanol (1 mL) was addedthereto. The mixture was stirred at room temperature for 18 hr. Theprecipitate was collected by filtration to give the title compound (218mg) as a white powder.

[0873]¹H-NMR(DMSO-d₆)δ1.14(3H,t,J=6.8 Hz), 2.05-2.28(2H,m),2.58-2.67(2H,m), 2.83-3.16(5H,m), 3.5-4.15(10H,m), 4.42-4.73(3H,m),7.24(2H,t,J=8.8 Hz), 7.34(2H,brs), 9.1(1H,brs), 10.35(1H,brs),11.95(1H,brs).

Example 156

[0874] Synthesis of3-{(2S,4S)-4-[1-(4-nitrophenyl)-4-piperidinyl]amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0875] (1) 1,4-Dioxa-8-azaspiro[4,5]decane (7.88 g) was dissolved inN-methyl-2-pyrrolidine (50 mL), and diisopropylethylamine (9.5.8 mL) and4-fluoronitrobenzene (7.06 g) were successively added. The mixture wasstirred at room temperature for 2 hr. The reaction mixture was added toiced water, and the precipitated solid was collected by filtration togive N-(4-nitrophenyl)-4-piperidone ethylene ketal (10.6 g) as a yellowpowder.

[0876] (2) The above-mentioned compound (9.25 g) was suspended inacetone (100 mL), and p-toluenesulfonic acid monohydrate (7.32 g) andhydrochloric acid (20 mL) were successively added. The mixture wasstirred at room temperature for 18 hr. Aqueous sodium hydroxide solutionwas added to the reaction mixture and the precipitate was collected byfiltration to give [1-(4-nitrophenyl)-4-piperidinyl]amine (6.48 g) as ayellow powder.

[0877] (3) Using the above-mentioned compound (6.17 g) and the titlecompound (4.22 g) of Reference Example 10, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[1-(4-nitrophenyl)-4-piperidinyl]amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(7.26 g) was obtained.

[0878] (4) The above-mentioned compound (524 mg) was dissolved in ethylacetate (2.07 mL), and 4 mol/L hydrochloric acid-ethyl acetate (1.04 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The precipitate was collected by filtration to give the titlecompound (406 mg) as a yellow powder.

[0879]¹H-NMR(DMSO-d₆)δ1.53-1.79(2H,m), 2.02-2.25(3H,m), 2.88-3.01(5H,m),3.35-3.96(5H,m), 3.96-4.28(3H,m), 4.39-4.78(3H,m), 7.08(2H,d,J=9.6 Hz),8.07(2H,d,J=9.3 Hz).

Example 157

[0880] Synthesis of3-{(2S,4S)-4-{N-methyl-N-[1-(4-nitrophenyl)-4-piperidinyl]amino}-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0881] (1) Using3-{(2S,4S)-1-tert-butoxycarbonyl-4-[1-(4-nitrophenyl)-4-piperidinyl]amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 156 (3), 1.01 g], and in the same manner as inExample 64 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-{N-methyl-N-[1-(4-nitrophenyl)-4-piperidinyl]amino}-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.04 g) was obtained.

[0882] (2) The above-mentioned compound (1.04 g) was dissolved inmethanol (4 ML), and 4 mol/L hydrochloric acid-1,4-dioxane (2 mL) wasadded thereto. The mixture was stirred at room temperature for 18 hr.The reaction mixture was concentrated under reduced pressure and theobtained solid was washed with ethanol to give the title compound (0.555g) as a yellow powder.

[0883]¹H-NMR(DMSO-d₆)δ1.50-1.90(2H,m), 1.95-2.40(3H,m), 2.68(3H,s),2.80-3.25(5H,m), 3.25-3.98(5H,m), 4.02-4.37(3H,m), 4.40-4.75(3H,m),7.09(2H,d,J=9.6 Hz), 8.07(2H,d,J=9.3 Hz).

Example 158

[0884] Synthesis of3-{(2s,4s)-4-{N-(4-cyanophenylmethyl)-N-[1-(4-nitrophenyl)-4-piperidinyl]amino}-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0885] (1) The product (1.01 g) of Example 156 (3) was dissolved inN-methyl-2-pyrrolidone (6 mL), and 4-cyanobenzyl bromide (0.392 g) anddisopropylethylamine (1.05 mL) were added thereto. The mixture wasstirred at 80° C. for 8 hr with heating. The reaction mixture was addedto saturated aqueous sodium hydrogencarbonate solution and the mixturewas extracted with ethyl acetate. The extract was dried and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-{N-(4-cyanophenylmethyl)-N-[1-(4-nitrophenyl)-4-piperidinyl]amino}-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.685 g) as a yellow oil.

[0886] (2) The above-mentioned compound (1.04 g) was dissolved in ethylacetate (4.41 mL), and 4 mol/L hydrochloric acid-ethyl acetate (2.20 mL)was added thereto. The mixture was stirred at room temperature for 18hr. The reaction mixture was added to saturated aqueous sodiumhydrogencarbonate solution and the mixture was extracted withchloroform. The extract was dried and concentrated under reducedpressure. The residue was purified by silica gel chromatography and wasdissolved in chloroform. 4 mol/L Hydrochloric acid-ethyl acetate (0.309mL) was added and the precipitate was collected by filtration to givethe title compound (0.249 g) as a yellow powder.

[0887]¹H-NMR(DMSO-d₆)δ1.34-2.35(5H,m), 2.45-3.20(7H,m), 3.20-4.25(8H,m),4.35-4.80(3H,m), 7.01(2H,d,J=9.6 Hz), 7.50-7.90(4H,m), 8.03(2H,d,J=9.3Hz), 8.87(1H,brs), 10.24(1H,brs).

Example 159

[0888] Synthesis of3-[(2S,4S)-4-(4-methyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrihydrochloride

[0889] The title compound (450 mg) of Reference Example 12,1-methylpiperazine (0.20 mL) and acetic acid (0.09 mL) were dissolved in1,2-dichloroethane (8 mL), and sodium triacetoxyborohydride (636 mg) wasadded thereto. The mixture was stirred at room temperature for 30 hr.Saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theextract was washed with brine and dried. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gelchromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-methyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(526 mg) as a white solid.

[0890] (2) The above-mentioned compound (522 mg) was dissolved inmethanol (25 mL), and 1.5 mol/L hydrochloric acid-methanol (25 mL) wasadded thereto. The mixture was stirred at room temperature for 38 hr.The reaction mixture was concentrated under reduced pressure and ethylacetate was added to the residue. The precipitate was collected byfiltration to give the title compound (355 mg) as a white powder.

[0891]¹H-NMR(DMSO-d₆)δ1.88-2.03(1H,m), 2.79(3H,s), 2.80-2.94(1H,m),2.98-3.93(15H,m), 4.43-4.77(3H,m), 9.10(1H,brs), 10.78(1H,brs),11.5(1H,brs).

Example 160

[0892] Synthesis of3-[(2S,4S)-4-(4-phenyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrihydrochloride

[0893] (1) Using the title compound (450 mg) and 1-phenylpiperazine(0.27 mL), and in the same manner as in Example 70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-phenyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(566 mg) was obtained as a white solid.

[0894] (2) The above-mentioned compound (442 mg) was dissolved in 1.5mol/L hydrochloric acid-methanol (10 mL), and the mixture was stirred atroom temperature for 20 hr. the reaction mixture was concentrated underreduced pressure and ethyl acetate was added to the residue. Theprecipitate was collected by filtration to give the title compound (418mg) as a white powder.

[0895]¹H-NMR(DMSO-d₆)δ2.35(1H,q,J=11.2 Hz), 2.94-3.95(15H,m),4.03-4.18(1H,m), 4.44-4.77(3H,m), 6.89(1H,t,J=7.3 Hz), 7.03(2H,d,J=8.0Hz), 7.28(2H,dd,J=8.0,7.3 Hz), 9.23(1H,brs), 10.94(1H,brs).

Example 161

[0896] Synthesis of1-[(2S,4S)-4-(4-phenyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]pyrrolidinetrihydrochloride

[0897] (1) Using the title compound (565 mg) of Reference Example 14 and1-phenylpiperazine (0.37 mL), and in the same manner as in Example 70(1),1-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-phenyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]pyrrolidine(832 mg) was obtained as a white solid.

[0898] (2) The above-mentioned compound (700 mg) was dissolved inmethanol (50 mL) and chloroform (50 mL), and 1.5 mol/L hydrochloricacid-methanol (50 mL) was added thereto. The mixture was stirred at roomtemperature for 5 days. The reaction mixture was concentrated underreduced pressure and methanol was added to the residue. The precipitatedsolid was collected by filtration to give the title compound (632 mg) asa white powder.

[0899]¹H-NMR(DMSO-d₆)δ1.73-1.98(4H,m), 2.29(1H,q,J=11.6 Hz),2.93-4.18(16H,m), 4.45-4.57(1H,m), 6.89(1H,t,J=8.0 Hz), 7.03(2H,d,J=8.0Hz), 7.28(2H,t,J=8.0 Hz), 9.13(1H,brs), 10.89(1H,brs).

Example 162

[0900] Synthesis of3-[(2S,4S)-4-(4-benzyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrihydrochloride

[0901] (1) The title compound (437 mg) of Reference Example 12,1-benzylpiperazine (303 mg) and acetic acid (0.085 mL) were dissolved in1,2-dichloroethane (6 mL), and sodium triacetoxyborohydride (650 mg) wasadded thereto. The mixture was stirred at room temperature for 5 hr.Saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theextract was washed with brine and dried. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gelchromatography to give3-[(2S,4S)-4-(4-benzyl-1-piperazinyl)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(556 mg) as a white solid.

[0902] (2) The above-mentioned compound (546 mg) was dissolved inmethanol (16 mL), and 4 mol/L hydrochloric acid-1,4-dioxane (8 mL) wasadded thereto. The mixture was stirred at room temperature for 15 hr.The precipitate was collected by filtration to give the title compound(412 mg) as a white powder.

[0903]¹H-NMR(DMSO-d₆)δ1.79-1.89(1H,m), 2.76-2.84(1H,m),2.90-3.90(15H,m), 4.35(2H,s), 4.45-4.73(3H,m), 7.45-7.47(3H,m),7.62-7.65(2H,m), 8.99(1H,brs), 10.45(1H,brs).

Example 163

[0904] Synthesis of3-{(2s,4S)-4-[4-(diphenylmethyl)-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinetrihydrochloride

[0905] (1) Using the title compound (402 mg) of Reference Example 12 and1-diphenylmethylpiperazine (405 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(diphenylmethyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(470 mg) was obtained as a white powder.

[0906] (2) Using the above-mentioned compound (470 mg), and in the samemanner as in Example 162 (2), the title compound (449 mg) was obtainedas a white powder.

[0907]¹H-NMR(DMSO-d₆)δ1.94-2.01(1H,m), 2.79-2.85(1H,m),3.03-3.92(15H,m), 4.43-4.73(3H,m), 4.48(1H,brs), 7.30-7.44(6H,m),7.88(4H,brs), 9.09(1H,brs), 10.50(1H,brs).

Example 164

[0908] Synthesis of3-{(2S,4S)-4-[4-(4-cyanophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0909] (1) Using the title compound (485 mg) of Reference Example 12 and1-(4-cyanophenyl)piperazine (335 mg), and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-cyanophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(492 mg) was obtained as a white powder.

[0910] (2) Formic acid (8 mL) was added to the above-mentioned compound(492 mg). The mixture was stirred at room temperature for 2 days. Thesolvent was evaporated under reduced pressure, and saturated aqueoussodium hydrogencarbonate solution was added to the residue. The mixturewas extracted with chloroform. The extract was washed with brine anddried. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel chromatography. 4 mol/L Hydrochloricacid-ethyl acetate was added and the precipitate was collected byfiltration to give the title compound (78 mg) as a white powder.

[0911]¹H-NMR(500 MHz,DMSO-d₆)δ2.20-2.27(1H,m), 2.95-3.16(3H,m),3.10-4.05(13H,m), 4.47-4.74(3H,m), 7.13(1H,d,J=8.8 Hz), 7.65(1H,d,J=8.8Hz), 9.13(1H,brs), 10.61(1H,brs).

Example 165

[0912] Synthesis of3-{(2S,4S)-4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0913] (1) Using the title compound (411 mg) of Reference Example 12 and1-(3-trifluoromethylphenyl)piperazine (378 mg), and in the same manneras in Example 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(700 mg) was obtained as a white powder.

[0914] (2) Using the above-mentioned compound (700 mg), and in the samemanner as in Example 162 (2), the title compound (553 mg) was obtainedas a white powder.

[0915]¹H-NMR(DMSO-d₆)δ2.25-2.36(1H,m), 3.00-4.10(16H,m),4.47-4.77(3H,m), 7.17(1H,d,J=7.8 Hz), 7.26-7.33(2H,m), 7.48(1H,t,J=7.8Hz), 9.25(1H,brs), 10.82(1H,brs).

Example 166

[0916] Synthesis of3-{(2S,4S)-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0917] (1) Using the title compound (513 mg) of Reference Example 12 and1-(4-methoxyphenyl)piperazine (394 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(536 mg) was obtained as a white powder.

[0918] (2) Using the above-mentioned compound (530 mg), and in the samemanner as in Example 162 (2), the title compound (567 mg) was obtainedas a white powder.

[0919]¹H-NMR(DMSO-d₆)δ2.28-2.39(1H,m), 3.00-3.17(3H,m),3.68-4.12(13H,m), 3.71(3H,s), 4.47-4.77(3H,m), 6.89(2H,d,J=9.0 Hz),7.05(2H,d,J=9.0 Hz), 9.22(1H,brs), 11.00(1H,brs).

Example 167

[0920] Synthesis of3-{(2S,4S)-4-[4-(4-hydroxyphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0921] (1) Using the title compound (515 mg) of Reference Example 12 and1-(4-hydroxyphenyl)piperazine (366 mg) and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-hydroxyphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(260 mg) was obtained as a pale-brown solid.

[0922] (2) The above-mentioned compound (259 mg) was dissolved indichloromethane (10 mL), and trifluoroacetic acid (3 mL) was addedthereto. The mixture was stirred at room temperature for 16 hr. Thereaction mixture was added to saturated aqueous sodium hydrogencarbonatesolution, and the mixture was extracted with chloroform. The extract waswashed with brine and dried. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography. Thereto was added 4 mol/L hydrochloric acid-ethylacetate and the precipitate was collected by filtration to give thetitle compound (15 mg) as a brown powder.

[0923]¹H-NMR(DMSO-d₆)δ2.18-2.28(1H,m), 2.97-4.00(16H,m),4.46-4.75(3H,m), 6.73(2H,d,J=8.7 Hz), 6.96-6.99(2H,m), 9.18(1H,brs),10.51(1H,brs).

Example 168

[0924] Synthesis of3-{(2S,4S)-4-[4-(2-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0925] (1) Piperazine (12.9 g) was dissolved in DMF (100 mL), and asolution of 2-fluoronitrobenzene (7.06 g) in DMF (30 mL) was addeddropwise. The mixture was stirred at room temperature for 3 hr. Thereaction mixture was added to water and the mixture was extracted withethyl acetate. The extract was washed with water and dried. The solventwas evaporated to give 1-(2-nitrophenyl)piperazine (7.7 g) as a red oil.

[0926] (2) Using the above-mentioned compound (414 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(690 mg) was obtained as a red oil.

[0927] (3) Using the above-mentioned compound (690 mg) and in the samemanner as in Example 161 (2), the title compound (433 mg) was obtainedas a yellow powder.

[0928]¹H-NMR(DMSO-d₆)δ2.19-2.40(1H,m), 2.90-4.24(16H,m),4.44-4.80(3H,m), 7.27(1H,t,J=7.5 Hz), 7.41(1H,d,J=7.8 Hz),7.68(1H,t,J=7.2 Hz), 7.92(1H,d,J=8.1 Hz).

Example 169

[0929] Synthesis of3-{(2S,4S)-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0930] (1) Using the title compound (465 mg) of Reference Example 12 and1-(4-nitrophenyl)piperazine (385 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(688 mg) was obtained as a yellow powder

[0931]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.79-1.99(1H,m),2.38-2.52(1H,m), 2.52-2.74(4H,m), 2.75-3.22(3H,m), 3.25-3.50(5H,m),3.60-4.20(3H,m), 4.36-4.82(3H,m), 6.82(2H,d,J=9.4 Hz), 8.12(2H,d,J=9.4Hz).

[0932] (2) Using the above-mentioned compound (560 mg), and in the samemanner as in Example 162 (2), the title compound (511 mg) was obtainedas a yellow powder.

[0933]¹H-NMR(DMSO-d₆)δ2.23-2.32(1H,m), 2.95-3.17(3H,m),3.57-4.04(13H,m), 4.47-4.76(3H,m), 7.15(2H,d,J=9.3 Hz), 8.12(2H,d,J=9.3Hz), 9.19(1H,brs), 10.68(1H,brs);[.]_(D) ²⁴-35(cl.0,H₂O).

Example 170

[0934] Synthesis of3-{(2S,4S)-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0935] (1) Using the title compound (409 mg) of Reference Example 12 and1-(4-fluorophenyl)piperazine (300 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(404 mg) was obtained as a white solid.

[0936] (2) Using the above-mentioned compound (402 mg), and in the samemanner as in Example 162 (2), the title compound (371 mg) was obtainedas a white powder.

[0937]¹H-NMR(DMSO-d₆)δ2.28-2.39(1H,m), 3.00-4.10(16H,m),4.47-4.76(3H,m), 7.02-7.14(4H,m), 9.20(1H,brs), 10.79(1H,brs).

Example 171

[0938] Synthesis of3-{(2S,4S)-4-[4-(2-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0939] (1) Using the title compound (430 mg) of Reference Example 12 and1-(2-chlorophenyl)piperazine (338 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(687 mg) was obtained as a white powder.

[0940] (2) Using the above-mentioned compound (687 mg), and in the samemanner as in Example 162 (2), the title compound (531 mg) was obtainedas a white powder.

[0941]¹H-NMR(DMSO-d₆)δ2.28-2.38(1H,m), 2.97-4.15(16H,m),4.47-4.77(3H,m), 7.12(1H,td,J=4.8,1.5 Hz), 7.21(1H,dd,J=4.8,1.5 Hz),7.35(1H,td,J=8.1,1.5 Hz), 7.46(1H,dd,J=8.1,1.5 Hz), 9.30(1H,brs),10.15(1H,brs).

Example 172

[0942] Synthesis of3-{(2S,4S)-4-[4-(3-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0943] (1) Using the title compound (476 mg) of Reference Example 12 and1-(3-chlorophenyl)piperazine (374 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(495 mg) was obtained as a white solid.

[0944] (2) Using the above-mentioned compound (494 mg), and in the samemanner as in Example 162 (2), the title compound (426 mg) was obtainedas a white powder.

[0945]¹H-NMR(DMSO-d₆)δ2.22-2.32(1H,m), 2.97-4.06(16H,m),4.47-4.76(3H,m), 6.88(1H,dd,J=8.1,1.8 Hz), 6.98(1H,dd,J=8.1,1.8 Hz),7.07(1H,d,J=1.8 Hz), 7.27(1H,t,J=8.1 Hz), 9.24(2H,brs);

Example 173

[0946] Synthesis of3-{(2S,4S)-4-[4-(4-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0947] (1) Using the title compound (473 mg) of Reference Example 12 and1-(4-chlorophenyl)piperazine (372 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(564 mg) was obtained as a white solid.

[0948] (2) Using the above-mentioned compound (554 mg), and in the samemanner as in Example 162 (2), the title compound (533 mg) was obtainedas a white powder.

[0949]¹H-NMR(DMSO-d₆)δ2.25-2.35(1H,m), 2.98-3.94(15H,m),4.04-4.10(1H,m), 4.45-4.75(3H,m), 7.05(2H,d,J=9.0 Hz), 7.30(2H,d,J=9.0Hz), 9.19(1H,brs), 10.63(1H,brs).

Example 174

[0950] Synthesis of3-{(2S,4S)-4-[4-(4-bromophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0951] (1) Using the title compound (332 mg) of Reference Example 12 and1-(4-bromophenyl)piperazine (300 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-bromophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(390 mg) was obtained as a white solid.

[0952] (2) Using the above-mentioned compound (388 mg), and in the samemanner as in Example 162 (2), the title compound (341 mg) was obtainedas a white powder.

[0953]¹H-NMR(500 MHz,DMSO-d₆)δ2.18-2.27(1H,m), 2.95-4.06(16H,m),4.47-4.74(3H,m), 6.98(2H,d,J=8.8 Hz), 7.40(2H,d,J=8.8 Hz), 9.15(1H,brs),10.50(1H,brs).

Example 175

[0954] Synthesis of3-{(2S,4s)-4-[4-(3,4-dicyanophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0955] (1) Using the title compound (561 mg) of Reference Example 12 and1-(3,4-dicyanophenyl)piperazine (475 mg), and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-dicyanophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(945 mg) was obtained as a pale-yellow powder.

[0956] (2) Using the above-mentioned compound (935 mg), and in the samemanner as in Example 167 (2), the title compound (508 mg) was obtainedas a pale-yellow powder.

[0957]¹H-NMR(DMSO-d₆)δ2.18-2.28(1H,m), 2.93-3.90(16H,m),4.46-4.75(3H,m), 7.41(1H,dd,J=9.0,2.7 Hz), 7.72(1H,d,J=2.7 Hz),7.90(1H,d,J=9.0 Hz), 9.19(1H,brs), 10.63(1H,brs).

Example 176

[0958] Synthesis of3-{(2S,4S)-4-[4-(3,4-dichlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0959] (1) using the title compound (540 mg) of Reference Example 12 and1-(3,4-dichlorophenyl)piperazine (500 mg), and in the same manner as inExample 162 (1),3-3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,4-dichlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(540 mg) was obtained as a white solid.

[0960] (2) Using the above-mentioned compound (540 mg), and in the samemanner as in Example 162 (2), the title compound (503 mg) was obtainedas a white solid.

[0961]¹H-NMR(DMSO-d₆)δ2.22-2.32(1H,m), 2.97-4.06(16H,m),4.47-4.76(3H,m), 7.03(1H,dd,J=9.0,2.7 Hz), 7.27(1H,d,J=2.7 Hz),7.46(1H,d,J=9.0 Hz), 9.20(1H,brs), 10.70(1H,brs).

Example 177

[0962] Synthesis of3-{(2S,4S)-4-[4-(3,5-dichlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0963] (1) Using the title compound (481 mg) of Reference Example 12 and1-(3,5-dichlorophenyl)piperazine (444 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,5-dichlorophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(523 mg) was obtained as a white solid.

[0964] (2) Using the above-mentioned compound (520 mg), and in the samemanner as in Example 162 (2), the title compound (442 mg) was obtainedas a white powder.

[0965]¹H-NMR(DMSO-d₆)δ2.20-2.30(1H,m), 2.97-4.06(16H,m),4.47-4.75(3H,m), 6.97(1H,s), 7.07(2H,s), 9.20(1H,brs), 10.60(1H,brs).

Example 178

[0966] Synthesis of3-{(2S,4S)-4-[4-(4-nitro-1-naphthyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0967] (1) Using the title compound (400 mg) of Reference Example 12 and1-(4-nitro-1-naphthyl)piperazine (414 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitro-1-naphthyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(600 mg) was obtained as a yellow powder.

[0968] (2) Using the above-mentioned compound (596 mg), and in the samemanner as in Example 162 (2), the title compound (449 mg) was obtainedas a pale-yellow powder.

[0969]¹H-NMR(DMSO-d₆)δ2.29-2.39(1H,m), 3.00-3.18(3H,m),3.57-4.17(13H,m), 4.48-4.78(3H,m), 7.29(1H,d,J=8.7 Hz), 7.73(1H,t,J=7.8Hz), 7.83(1H,t,J=7.8 Hz), 8.27(1H,d,J=8.4 Hz), 8.36(1H,d,J=8.4 Hz),8.52(1H,d,J=8.7 Hz), 9.20(1H,brs), 10.60(1H,brs).

Example 179

[0970] Synthesis of3-{(2S,4S)-4-[4-(2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0971] (1) Using the title compound (426 mg) of Reference Example 12 and1-(2-pyridyl)piperazine (0.26 mL), and in the same manner as in Example162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(375 mg) was obtained as a white solid.

[0972] (2) Using the above-mentioned compound (374 mg), and in the samemanner as in Example 162 (2), the title compound (466 mg) was obtainedas a white powder.

[0973]¹H-NMR(DMSO-d₆)δ2.26-2.37(1H,m), 3.00-3.16(3H,m),3.43-4.06(13H,m), 4.47-4.78(3H,m), 6.98(1H,t,J=6.0 Hz), 7.35(1H,d,J=9.0Hz), 7.96(1H,td,J=9.0,1.5 Hz), 8.13(1H,dd,J=6.0,1.5 Hz), 9.23(1H,brs),10.98(1H,brs).

Example 180

[0974] Synthesis of3-{(2S,4S)-4-[4-(4-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0975] (1) Using the title compound (601 mg) of Reference Example 12 and1-(4-pyridyl)piperazine (326 mg), and in the same manner as in Example70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(366 mg) was obtained.

[0976] (2) Using the above-mentioned compound (366 mg), and in the samemanner as in Example 161 (2), the title compound (133 mg) was obtainedas a white powder.

[0977]¹H-NMR(DMSO-d₆)δ2.03-2.30(1H,m), 2.79-4.30(16H,m),4.40-4.80(3H,m), 7.32(2H,d,J=7.5 Hz), 8.34(2H,d,J=7.2 Hz), 9.15(1H,brs),10.80(1H,brs), 14.00(1H,brs).

Example 181

[0978] Synthesis of3-{(2S,4S)-4-[4-(4-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0979] (1) Using the title compound (494 mg) of Reference Example 12 and1-(4-cyano-2-pyridyl)piperazine (371 mg), and in the same manner as inExample 154 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(431 mg) was obtained as a white solid.

[0980] (2) Using the above-mentioned compound (424 mg), and in the samemanner as in Example 167 (2), the title compound (194 mg) was obtainedas a pale-yellow powder.

[0981]¹H-NMR(500 MHz,DMSO-d₆)δ2.32-2.39(1H,m), 3.00-3.16(3H,m),3.25-4.07(13H,m), 4.48-4.75(3H,m), 7.10(1H,dd,J=5.1,0.8 Hz),7.50(1H,d,J=0.8 Hz), 8.36(1H,d,J=5.1 Hz), 9.22(1H,brs), 10.91(1H,brs).

Example 182

[0982] Synthesis of1-{(2S,4S)-4-[4-(4-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}pyrrolidinetrihydrochloride

[0983] (1) Using the title compound (527 mg) of Reference Example 14 and1-(4-cyano-2-pyridyl)piperazine (422 mg), and in the same manner as inExample 70 (1),1-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}pyrrolidine(502 mg) was obtained as a pale-yellow solid.

[0984] (2) Using the above-mentioned compound (491 mg), and in the samemanner as in Example 167 (2), the title compound (134 mg) was obtainedas a pale-yellow powder.

[0985]¹H-NMR(500 MHz,DMSO-d₆)δ1.83-1.96(4H,m), 2.25-2.30(1H,m),2.98-3.02(1H,m), 3.20-3.56(10H,m), 3.70-3.72(2H,m), 4.04-4.08(1H,m),4.30-4.54(2H,m), 4.50-4.54(1H,m), 7.10(1H,dd,J=5.1,0.8 Hz),7.50(1H,d,J=0.8 Hz), 8.36(1H,d,J=5.1 Hz), 9.12(1H,brs), 10.73(1H,brs).

Example 183

[0986] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[0987] (1) Using the title compound (740 mg) of Reference Example 12 and1-(5-cyano-2-pyridyl)piperazine (516 mg), and in the same manner as inExample 154 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(772 mg) was obtained as a white powder.

[0988]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.86-1.98(1H,m),2.45-2.60(5H,m), 2.83-3.25(3H,m), 3.31-3.39(1H,m), 3.60-3.79(5H,m),3.81-3.99(2H,m), 4.40-4.85(3H,m), 6.58(1H,d,J=9.0 Hz),7.61(1H,dd,J=9.0,2.1 Hz), 8.40(1H,d,J=2.1 Hz).

[0989] (2) Using the above-mentioned compound (744 mg), and in the samemanner as in Example 167 (2), the title compound (202 mg) was obtainedas a pale-yellow powder.

[0990]¹H-NMR(DMSO-d₆)δ2.28-2.39(1H,m), 2.97-3.16(3H,m),3.35-4.10(13H,m), 4.47-4.76(3H,m), 7.11(1H,d,J=9.3 Hz),7.98(1H,dd,J=9.3,2.1 Hz), 8.57(1H,d,J=2.1 Hz), 9.25(1H,brs),10.91(1H,brs);[.]_(D) ²³-32(c1.0,H₂O).

Example 184

[0991] Synthesis of3-{(2S,4S)-4-[4-(5-trifluoromethyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0992] (1) Piperazine (12.9 g) was suspended in N-methyl-2-pyrrolidone(130 mL), and a solution of 2-chloro-5-trifluoromethylpyridine (9.08 g)in N-methyl-2-pyrrolidone (30 mL) was added dropwise. The mixture wasstirred at room temperature for 18 hr. The reaction mixture was added towater and the mixture was extracted with ethyl acetate. The extract waswashed with water and dried. The solvent was evaporated under reducedpressure to give 1-(5-trifluoromethyl-2-pyridyl)piperazine (11.5 g) as awhite solid.

[0993] (2) Using the above-mentioned compound (462 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-trifluoromethyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(379 mg) as an oil.

[0994] (3) Using the above-mentioned compound (368 mg), and in the samemanner as in Example 161 (2), the title compound (276 mg) was obtainedas a white powder.

[0995]¹H-NMR(DMSO-d₆)δ2.20-2.48(1H,m), 2.87-5.00(19H,m), 7.14(1H,d,J=9.0Hz), 7.92(1H,dd,J=9.3,2.4 Hz), 8.49(1H,d,J=0.6 Hz).

Example 185

[0996] Synthesis of3-{(2S,4S)-4-[4-(5-nitro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[0997] (1) Using 2-chloro-5-nitropyridine (7.93 g), and in the samemanner as in Example 184 (1), 1-(5-nitro-2-pyridyl)piperazine (9.3 g)was obtained as a yellow powder.

[0998] (2) Using the above-mentioned compound (416 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-nitro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(754 mg) was obtained as a yellow powder.

[0999] (3) Using the above-mentioned compound (693 mg), and in the samemanner as in Example 161 (2), the title compound (475 mg) was obtainedas a yellow powder.

[1000]¹H-NMR(DMSO-d₆)δ2.00-2.34(1H,m), 2.75-4.10(16H,m),4.40-4.80(3H,m), 7.09(1H,d,J=9.6 Hz), 8.32(1H,dd,J=9.6,3.0 Hz),9.01(1H,d,J=3.0 Hz), 9.18(1H,brs), 10.50(1H,brs).

Example 186

[1001] Synthesis of1-{(2S,4S)-4-[4-(5-nitro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}pyrrolidinetrihydrochloride

[1002] (1) Using 1-(5-nitro-2-pyridyl)piperazine [product of Example 185(1), 625 mg] and the title compound (565 mg) of Reference Example 14,and in the same manner as in Example 70 (1),1-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-nitro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}pyrrolidine(632 mg) was obtained as a yellow powder.

[1003] (2) The above-mentioned compound (522 mg) was dissolved inmethanol (10 mL) and chloroform (2.5 mL), and 4 mol/L hydrochloricacid-ethyl acetate (5 mL) was added thereto. The mixture was stirred atroom temperature for 18 hr. The reaction mixture was concentrated underreduced pressure, and the residue was washed with ethanol to give thetitle compound (395 mg) as a yellow powder.

[1004]¹H-NMR(DMSO-d₆)δ1.70-2.04(4H,m), 2.09-2.36(1H,m), 2.86-3.07(1H,m),3.20-5.00(14H,m), 7.11(1H,d,J=9.6 Hz), 8.33(1H,dd,J=9.6,3.0 Hz),9.02(1H,d,J=2.7 Hz), 9.11(1H,brs), 10.80(1H,brs).

Example 187

[1005] Synthesis of3-{(2S,4S)-4-[4-(5-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1006] (1) Using the title compound (340 mg) of Reference Example 12 and1-(5-chloro-2-pyridyl)piperazine (268 mg), and in the same manner as inExample 162 (1),3-{(2s,4s)-1-tert-butoxycarbonyl-4-[4-(5-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(421 mg) was obtained as a white solid.

[1007] (2) Using the above-mentioned compound (418 mg), and in the samemanner as in Example 162 (2), the title compound (262 mg) was obtainedas a white powder.

[1008]¹H-NMR(500 MHz,DMSO-d₆)δ2.26-2.31(1H,m), 2.97-4.40(16H,m),4.47-4.73(3H,m), 7.03(1H,d,J=9.1 Hz), 7.71(1H,dd,J=9.1,2.5 Hz),8.18(1H,d,J=2.5 Hz), 9.18(1H,brs), 10.57(1H,brs).

Example 188

[1009] Synthesis of3-{(2S,4S)-4-[4-(2-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1010] (1) Using the title compound (488 mg) of Reference Example 12 and1-(2-quinolyl)piperazine (416 mg), and in the same manner as in Example162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(724 mg) was obtained as a white solid.

[1011] (2) Using the above-mentioned compound (720 mg), and in the samemanner as in Example 162 (2), the title compound (560 mg) was obtainedas a white powder.

[1012]¹H-NMR(DMSO-d₆)δ2.20-2.30(1H,m), 2.96-3.17(3H,m),3.64-4.40(13H,m), 4.47-4.76(3H,m), 7.50(1H,t,J=7.5 Hz), 7.60(1H,d,J=9.6Hz), 7.77(1H,t,J=7.8 Hz), 7.93(1H,d,J=7.5 Hz), 8.15-8.20(1H,m),8.44(1H,d,J=9.6 Hz), 9.21(1H,brs), 10.68(1H,brs).

Example 189

[1013] Synthesis of3-{(2S,4S)-4-[4-(4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1014] (1) Piperazine (13.2 g) was melted by heating at 140° C., and4-chloroquinoline (2.5 g) was added thereto. The mixture was stirred at140° C. for 30 min. The reaction mixture was added to iced water, andthe mixture was extracted with chloroform to give1-(4-quinolyl)piperazine (3.45 g) as a pale-yellow oil.

[1015] (2) Using the above-mentioned compound (469 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(995 mg) was obtained.

[1016] (3) Using the above-mentioned compound (995 mg), and in the samemanner as in Example 186 (2), the title compound (392 mg) as obtained asa white powder.

[1017]¹H-NMR(DMSO-d₆)δ2.16-2.40(1H,m), 2.70-4.30(16H,m),4.40-4.80(3H,m), 7.37(1H,d,J=6.9 Hz), 7.77(1H,t,J=8.1 Hz),8.04(1H,t,J=8.4 Hz), 8.21(1H,d,J=8.7 Hz), 8.85(1H,d,J=6.9 Hz).

Example 190

[1018] Synthesis of3-{(2S,4S)-4-[4-(1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1019] (1) Using the title compound (606 mg) of Reference Example 12 and1-(1-isoquinolyl)piperazine (692 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(216 mg) was obtained as a white solid.

[1020] (2) Using the above-mentioned compound (215 mg), and in the samemanner as in Example 162 (2), the title compound (99 mg) was obtained asa pale-yellow powder.

[1021]¹H-NMR(500 MHz,DMSO-d₆)δ2.25-2.30(1H,m), 3.00-3.17(3H,m),3.59-3.95(12H,m), 4.13-4.18(1H,m), 4.49-4.77(3H,m), 7.59(1H,d,J=6.1 Hz),7.71-7.74(1H,m), 7.86-7.89(1H,m), 8.02(1H,d,J=8.2 Hz), 8.08(1H,d,J=6.1Hz), 8.21(1H,d,J=8.5 Hz), 9.25(1H,brs), 10.89(1H,brs).

Example 191

[1022] Synthesis of3-{(2S,4S)-4-[4-(2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1023] (1) Using the title compound (0.655 g) of Reference Example 12and 1-(2-trifluoromethyl-4-quinolyl)piperazine (0.735 g), and in thesame manner as in Example 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.23 g) was obtained as a pale-yellow powder:¹H-NMR(DMSO-d₆)δ1.33(4.5H,s), 1.41(4.5H,s), 1.55-1.64(1H,m),2.60-2.78(5H,m), 2.90-3.15(4H,m), 3.33-3.38(4H,m), 3.67-3.85(3H,m),4.04-4.69(3H,m), 7.25(1H,s), 7.70(1H,t,J=8.1 Hz), 7.81-7.87(1H,m),8.07(2H,d,J=8.4 Hz).

[1024] (2) Using the above-mentioned compound (1.23 g), and in the samemanner as in Example 162 (2), the title compound (1.06 g) was obtainedas a pale-yellow powder.

[1025]¹H-NMR(DMSO-d₆)δ2.28-2.38(1H,m), 3.00-3.18(3H,m),3.48-4.15(13H,m), 4.48-4.78(3H,m), 7.39(1H,s), 7.75(1H,t,J=7.5 Hz),7.89(1H,t,J=7.5 Hz), 8.11-8.16(2H,m), 9.23(1H,brs),10.68(1H,brs);[.]_(D) ²⁴-32(c1.0,H₂O).

Example 192

[1026] Synthesis of3-((2S,4S)-4-[4-(2-benzoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1027] (1) Using 2-chlorobenzoxazole (7.68 g) and piperazine (12.9 g),and in the same manner as in Example 168 (1),1-(2-benzoxazolyl)piperazine (2.4 g) was obtained as a white solid.

[1028] (2) Using the above-mentioned compound (610 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(2-benzoxazolyl)-1-tert-butoxycarbonyl-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(526 mg) was obtained as a white powder.

[1029] (3) Using the above-mentioned compound (416 mg), and in the samemanner as in Example 186 (2), the title compound (286 mg) was obtainedas a white powder.

[1030]¹H-NMR(DMSO-d₆)δ2.20-2.42(1H,m), 2.89-3.20(3H,m),3.25-4.35(13H,m), 4.40-4.80(3H,m), 7.10(1H,td,J=7.5,1.2 Hz),7.22(1H,td,J=7.8,1.2 Hz), 7.37(1H,dd,J=7.8,0.6 Hz), 7.47(1H,d,J=7.8 Hz),9.25(1H,brs), 11.00(1H,brs).

Example 193

[1031] Synthesis of3-{(2S,4S)-4-[4-(2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1032] (1) Using 2-chlorobenzothiazole (8.48 g) and piperazine (43.1 g),and in the same manner as in Example 189 (1),1-(2-benzothiazolyl)piperazine (10.9 g) was obtained.

[1033] (2) Using the above-mentioned compound (482 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(2-benzothiazolyl)-1-piperazinyl]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(798 mg) was obtained as a white powder.

[1034] (3) Using the above-mentioned compound (606 mg), and in the samemanner as in Example 186 (2), the title compound (591 mg) was obtainedas a white powder.

[1035]¹H-NMR(DMSO-d₆)δ2.20-2.44(1H,m), 2.90-3.20(3H,m),3.35-4.30(13H,m), 4.42-4.82(3H,m), 7.16(1H,t,J=7.2 Hz), 7.35(1H,t,J=7.2Hz), 7.55(1H,d,J=7.8 Hz), 7.86(1H,d,J=7.5 Hz), 9.25(1H,brs),10.90(1H,brs).

Example 194

[1036] Synthesis of3-{(2S,4S)-4-[4-(benz-2-oxa-1,3-diazol-5-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1037] (1) Using 5-chlorobenzofurazan (0.500 g) and piperazine (2.79 g),and in the same manner as in Example 189 (1),1-(benz-2-oxa-1,3-diazol-5-yl)piperazine (0.433 g) was obtained.

[1038] (2) Using the above-mentioned compound (433 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(benz-2-oxa-1,3-diazol-5-yl)-1-tert-butoxycarbonyl-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(500 mg) was obtained as a yellow powder.

[1039] (3) Using the above-mentioned compound (438 mg), and in the samemanner as in Example 186 (2), the title compound (409 mg) was obtainedas a yellow powder.

[1040]¹H-NMR(DMSO-d₆)δ2.10-2.40(1H,m), 2.80-4.30(16H,m),4.40-4.80(3H,m), 7.02(1H,s), 7.72(1H,dd,J=9.9,1.5 Hz), 7.94(1H,d,J=9.9Hz).

Example 195

[1041] Synthesis of3-{(2S,4S)-4-[4-(4-nitrobenzoyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1042] (1) Using the title compound (454 mg) of Reference Example 12 and1-(4-nitrobenzoyl)piperazine (426 mg), and in the same manner as inExample 162 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitrobenzoyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(500 mg) was obtained as a white solid.

[1043] (2) Using the above-mentioned compound (496 mg), and in the samemanner as in Example 162 (2), the title compound (242 mg) was obtainedas a white powder.

[1044]¹H-NMR(DMSO-d₆)δ2.15-2.22(1H,m), 2.90-2.94(1H,m),3.07-3.93(15H,m), 4.46-4.73(3H,m), 7.75(2H,d,J=8.6 Hz), 8.32(2H,d,J=8.6Hz), 9.15(1H,brs), 10.63(1H,brs).

Example 196

[1045] Synthesis of3-{(2S,4S)-4-[4-(4-nitrophenyl)-1,4-diazepam-1-yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1046] (1) Homopiperazine (15.0 g) was dissolved inN-methyl-2-pyrrolidine (50 mL), and 4-fluoronitrobenzene (7.06 g) wasadded thereto. The mixture was stirred at room temperature for 30 min.The reaction mixture was added to iced water, and the precipitate wascollected by filtration to give N-(4-nitrophenyl)-1,4-diazepam (10.9 g)as a yellow powder.

[1047] (2) Using the above-mentioned compound (443 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert.butoxycarbonyl-4-[4-(4-nitrophenyl)-1,4-diazepam-1-yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(429 mg) was obtained as a yellow powder.

[1048] (3) Using the above-mentioned compound (398 mg), and in the samemanner as in Example 161 (2), the title compound (118 mg) was obtainedas a yellow powder.

[1049]¹H-NMR(DMSO-d₆)δ1.80-2.60(3H,m), 2.70-4.20(12H,m),4.38-4.78(3H,m), 6.89(2H,d,J=9.3 Hz), 8.09(2H,d,J=9.3 Hz).

Example 197

[1050] Synthesis of3-{(2S,4S)-4-[4-(2-trifluoromethyl-4-quinolyl)-1,4-diazepam-1-yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1051] (1) Using 4-chloro-2-trifluoromethylquinoline (5.00 g) andhomopiperazine (20.7 g), and by reaction in the same manner as inExample 196 (1) at 60° C., N-(2-trifluoromethyl-4-quinolyl)-1,4-diazepam(6.11 g) was obtained as a yellow solid.

[1052] (2) Using the above-mentioned compound (0.83 g) and the titlecompound (0.703 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-4-quinolyl)-1,4-diazepam-1-yl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.35 g) was obtained as a white powder.

[1053] (3) Using the above-mentioned compound (1.35 g), and in the samemanner as in Example 133 (2), the title compound (1.21 g) was obtainedas a pale-yellow powder.

[1054]¹H-NMR(500 MHz,DMSO-d₆)δ2.19-2.49(3H,m), 2.96-3.19(3H,m),3.30-4.28(13H,m), 4.48-4.76(3H,m), 7.17(1H,s), 7.67(1H,t,J=7.6 Hz),7.83(1H,t,J=7.6 Hz), 8.05-8.10(2H,m), 9.14(1H,brs), 10.91(1H,brs),12.51(1H,brs)

Example 198

[1055] Synthesis of3-{(2S,4S)-4-[4-(2-hydroxyethyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1056] (1) Using 1-piperazineethanol (147 mg) and the title compound(307 mg) of Reference Example 12, and in the same manner as in Example70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-hydroxyethyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(354 mg) was obtained as an oil.

[1057] (2) Using the above-mentioned compound (350 mg), and in the samemanner as in Example 132 (2), deprotection was conducted. The solventwas evaporated under reduced pressure, and the residue was dissolved inethyl acetate (5 mL). 4 mol/L Hydrochloric acid-ethyl acetate (1.0 mL)was added thereto, and the precipitated solid was collected byfiltration to give the title compound (158 mg) as a white powder.

[1058]¹H-NMR(500 MHz,DMSO-d₆)δ1.91(1H,m), 2.78-3.93(20H,m),4.46-4.74(3H,m), 8.97(1H,brs), 10.80(1H,brs), 11.97(1H,brs).

Example 199

[1059] Synthesis of3-[(2S,4S)-4-(4-pivaloyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[1060] (1) Using N-benzyloxycarbonyl-L-trans-4-hydroxyproline (25.0 g),and in the same manner as in Reference Examples 9 and 12,3-((2S)-1-benzyloxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(10.9 g) was obtained as white crystals.

[1061] (2) Using the above-mentioned compound (4.05 g) and1-tert-butoxycarbonylpiperazine (2.48 g), and in the same manner as inExample 70 (1),3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(4.64 g) was obtained as a white powder.

[1062] (3) The above-mentioned compound (4.04 g) was deprotected in thesame manner as in Example 132 (2). The solvent was evaporated underreduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted withchloroform, and the extract was dried and concentrated under reducedpressure to give3-[(2S,4S)-1-benzyloxycarbonyl-4-(1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(3.10 g) as a white powder.

[1063] (4) The above-mentioned compound (405 mg) and triethylamine (170μL) were dissolved in chloroform (4 mL), and pivaloyl chloride (126 μL)was added thereto at room temperature. The mixture was stirred for 3 hr.Water was added to the reaction mixture and the mixture was extractedwith chloroform. The extract was dried and the mixture was concentratedunder reduced pressure to give3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-pivaloyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(430 mg) as a white solid.

[1064] (5) The above-mentioned compound (423 mg) was dissolved intrifluoroacetic acid, and thioanisole (0.6 mL) was added thereto. Themixture was stirred at room temperature for 21 hr. Diethyl ether wasadded to the reaction mixture, and the precipitated solid was collectedby filtration and purified by HPLC. This was converted to hydrochloridewith 4 mol/L hydrochloric acid-ethyl acetate to give the title compound(95 mg) as a white powder.

[1065]¹H-NMR(500 MHz,DMSO-d₆)δ1.20(9H,s), 2.12-2.33(1H,m),2.85-4.05(16H,m), 4.48-4.73(3H,m), 9.08(1H,brs), 10.73(1H,brs).

Example 200

[1066] Synthesis of3-((2S,4S)-4-(4-methoxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[1067] (1) Using3-[(2S,4S)-1-benzyloxycarbonyl-4-(I-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine[product of Example 199 (3), 405 mg] and methyl chlorocarbonate (79 μL),and in the same manner as in Example 199 (4),3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-methoxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(413 mg) was obtained as a white solid.

[1068] (2) Using the above-mentioned compound (407 mg), and in the samemanner as in Example 199 (5), the title compound (43 mg) was obtained asa brown powder.

[1069]¹H-NMR(500 MHz,DMSO-d₆)δ2.13-2.43(1H,m), 2.85-4.05(16H,m),3.63(3H,s), 4.47-4.74(3H,m), 9.08(1H,brs), 10.73(1H,brs).

Example 201

[1070] Synthesis of3-[(2S,4S)-4-(4-isobutyloxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[1071] (1) Using the product (405 mg) of Example 199 (3) and isobutylchlorocarbonate (133 μL), and in the same manner as in Example 199 (4),3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-isobutyloxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(421 mg) was obtained as a white solid.

[1072] (2) Using the above-mentioned compound (416 mg), and in the samemanner as in Example 199 (5), the title compound (59 mg) was obtained asa white powder.

[1073]¹H-NMR(500 MHz,DMSO-d₆)δ0.90(6H,d,J=6.8 Hz), 1.81-1.97(1H,m),2.19-2.39(1H,m), 2.90-4.20(16H,m), 3.83(2H,d,J=6.5 Hz), 4.47-4.74(3H,m),9.12(1H,brs), 11.07(1H,brs).

Example 202

[1074] Synthesis of3-[(2S,4S)-4-(4-benzyloxycarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[1075] (1) Using 1-benzyloxcarbonylpiperazine (217 mg) and the titlecompound (307 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-[(2S,4S)-4-(4-benzyloxycarbonyl-1-piperazinyl)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(500 mg) was obtained as a white powder.

[1076] (2) Using the above-mentioned compound (490 mg), and in the samemanner as in Example 133 (2), the title compound (399 mg) was obtainedas a white powder.

[1077]¹H-NMR(500 MHz,DMSO-d₆)δ2.10-2.30(1H,m), 1.70-4.20(16H,m),4.46-4.73(3H,m), 5.11(2H,s), 7.31-7.42(5H,m), 9.06(1H,brs),10.67(1H,brs), 12.50(1H,brs).

Example 203

[1078] Synthesis of3-[(2S,4S)-4-(4-cyclohexylaminocarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[1079] (1) Using the product (405 mg) of Example 199 (3) and cyclohexylisocyanate (127 μL), and in the same manner as in Example 199 (4),3-[(2S,4S)-1-benzyloxycarbonyl-4-(4-cyclohexylaminocarbonyl-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(296 mg) was obtained as a white solid.

[1080] (2) Using the above-mentioned compound (296 mg), and in the samemanner as in Example 199 (5), the title compound (85 mg) was obtained asa white powder.

[1081]¹H-NMR(500 MHz,DMSO-d₆)δ1.00-1.29(5H,m), 1.53-1.80(5H,m),2.12-2.32(1H,m), 2.80-4.20(17H,m), 4.47-4.73(3H,m), 6.48(1H,brs),9.09(1H,brs), 10.65(1H,brs), 12.18(1H,brs).

Example 204

[1082] Synthesis of3-{(2S,4S)-4-[4-(2,6-dimethylphenyl)aminocarbonyl-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1083] (1) Using the product (405 mg) of Example 199 (3) and2,6-dimethylphenyl isocyanate (142 μL), and in the same manner as inExample 199 (4),3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(2,6-dimethylphenyl)aminocarbonyl-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(517 mg) was obtained as a white powder.

[1084] (2) Using the above-mentioned compound (503 mg), and in the samemanner as in Example 199 (5), the title compound (166 mg) was obtainedas a white powder.

[1085]¹H-NMR(500 MHz,DMSO-d₆)δ2.15(6H,s), 2.09-2.29(1H,m),2.85-4.20(16H,m), 4.48-4.73(3H,m), 7.04(3H,m), 8.16(1H,s), 9.07(1H,brs),10.61(1H,brs).

Example 205

[1086] Synthesis of3-{(2S,4S)-4-[4-(8-quinolinesulfonyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1087] (1) 1-tert-Butoxycarbonylpiperazine (2.22 g) and triethylamine(2.0 mL) were dissolved in dichloromethane (100 mL), and8-quinolinesulfonyl chloride (2.71 g) was added thereto. The mixture wasstirred at room temperature for 14 hr. 10% citric acid solution wasadded to the reaction mixture and the mixture was extracted withchloroform. The extract was washed with brine, dried and concentratedunder reduced pressure. The residue was dissolved in dichloromethane (20mL), and trifluoroacetic acid (5 mL) was added thereto. The mixture wasstirred at room temperature for 1.5 hr. The reaction mixture wasconcentrated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with chloroform, and the extract was dried and concentratedunder reduced pressure to give 1-(8-quinolinesulfonyl)piperazine (0.73g) as a white solid.

[1088] (2) using the above-mentioned compound (0.725 g) and the titlecompound (0.714 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(8-quinolinesulfonyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.34 g) was obtained as a white powder.

[1089] (3) Using the above-mentioned compound (1.34 g), and in the samemanner as in Example 133 (2), the title compound (0.56 g) was obtainedas a pale-yellow powder.

[1090]¹H-NMR(500 MHz,DMSO-d₆)δ2.01-2.21(1H,m), 2.80-3.95(16H,m),4.43-4.72(3H,m), 7.74(1H,dd,J=8.3,4.2 Hz), 7.79(1H,t,J=7.9 Hz),8.35-8.40(2H,m), 8.58(1H,dd,J=8.3,1.7 Hz), 9.00(1H,brs),9.06(1H,dd,J=4.2,1.7 Hz), 10.60(1H,brs).

Example 206

[1091] Synthesis of3-{(2S,4S)-4-[4-(1-ethoxycarbonyl-4-piperidinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetetrahydrochloride

[1092] (1) Using 1-(9-fluorenylmethoxycarbonyl)piperazine (1.47 g) andthe title compound (1.30 g) of Reference Example 12, and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(9-fluorenylmethoxycarbonyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.68 g) was obtained as a white powder.

[1093] (2) The above-mentioned compound (1.68 g) was dissolved indichloromethane (30 mL), and piperidine (1.5 mL) was added thereto atroom temperature. The mixture was stirred for 4 hr. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(206 mg) as a white solid.

[1094] (3) Using the above-mentioned compound (202 mg) and1-ethoxycarbonyl-4-piperidone (90 μL), and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-ethoxycarbonyl-4-piperidinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(168 mg) was obtained as a white powder.

[1095] (4) Using the above-mentioned compound (168 mg), and in the samemanner as in Example 133 (2), the title compound (113 mg) was obtainedas a white powder.

[1096]¹H-NMR(500 MHz,DMSO-d₆)δ1.18(3H,t,J=7.1 Hz), 1.53-1.65(2H,m),1.81-1.95(1H,m), 2.01-2.21(2H,m), 2.70-4.20(21H,m), 4.04(2H,q,J=7.1 Hz),4.47-4.73(3H,m), 8.89(1H,brs), 10.39(1H,brs), 11.46(1H,brs).

Example 207

[1097] Synthesis of3-{(2S,4R)-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1098] (1)3-((2S,4R)-4-Amino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(title compound of Reference Example 15, 1 g) was dissolved inN-methyl-2-pyrrolidone (20 mL), andN,N-bis{2-[(methylsulfonyl)oxy]ethyl}-4-nitroaniline (1.27 g) andN,N-diisopropylethylamine (1.73 mL) were added thereto. The mixture wasstirred at 80° C. for 24 hr with heating. The reaction mixture was addedto saturated aqueous sodium hydrogencarbonate solution, and the mixturewas extracted with ethyl acetate. The extract was washed with brine andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give3-{(2S,4R)-1-tert-butoxycarbonyl-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine.

[1099] (2) This was dissolved in methanol (20 mL) and chloroform (10mL), and 4 mol/L hydrochloric acid-ethyl acetate (10 mL) was addedthereto. The mixture was stirred for 2 hr. The reaction mixture wasconcentrated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with chloroform and the extract was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givea free base (161 mg) of the title compound. This was dissolved inethanol (5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (0.21 mL)was added thereto. The solvent was evaporated under reduced pressure togive the title compound (128 mg) as a yellow powder.

[1100]¹H-NMR(DMSO-d₆)δ2.22-2.46(1H,m), 2.75-2.99(1H,m), 3.00-3.20(2H,m),3.20-4.30(13H,m), 4.40-5.07(3H,m), 7.16(2H,d,J=9.3 Hz), 8.12(2H,d,J=9.3Hz).

Example 208

[1101] Synthesis of3-{(2S,4S)-4-[4-(4-trifluoromethylphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1102] (1) Using the title compound (450 mg) of Reference Example 12 and1-(4-trifluoromethylphenyl)piperazine (414 mg), and in the same manneras in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-trifluoromethylphenyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(772 mg) was obtained as a white solid.

[1103] (2) The above-mentioned compound (766 mg) was dissolved inmethanol (5 mL), and 1.1 mol/L hydrochloric acid-methanol (14 mL) wasadded thereto. The mixture was stirred at room temperature for 4 days.The reaction mixture was concentrated under reduced pressure, and ethylacetate was added to the residue. The precipitated solid was collectedby filtration to give the title compound (680 mg) as a pale-brownpowder.

[1104]¹H-NMR(DMSO-d₆)δ2.27-2.40(1H,m), 2.96-4.16(16H,m),4.46-4.77(3H,m), 7.18(2H,d,J=8.8), 7.58(2H,d,J=8.8), 9.22(1H,brs),10.73(1H,brs).

Example 209

[1105] Synthesis of3-{(2S,4S)-4-[4-(3-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1106] (1) Piperazine (125 g) was melted by heating at 150° C. and2-chloro-3-cyanopyridine (20.0 g) was added thereto. The mixture wasstirred at 110° C. for 2 hr. Water was added to the reaction mixture andthe mixture was extracted with chloroform. The extract was washed withbrine, dried and concentrated under reduced pressure to give1-(3-cyano-2-pyridyl)piperazine (24.2 g) as a brown solid.

[1107] (2) Using the above-mentioned compound (0.621 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.42 g) was obtained as a white solid.

[1108]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.83-1.97(1H,m),2.40-2.51(1H,m), 2.53-2.72(4H,m), 2.82-3.22(3H,m), 3.33(1H,t,J=9.9 Hz),3.35-4.14(7H,m), 4.38-4.79(3H,m), 6.76(1H,dd,J=7.6,4.7 Hz),7.77(1H,dd,J=7.6,1.7 Hz), 8.34(1H,dd,J=4.7,1.7 Hz).

[1109] (3) The above-mentioned compound (1.42 g) was dissolved in ethylacetate (7.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (7.5 mL)was added thereto. The mixture was stirred at room temperature for 12hr. The precipitated solid was collected by filtration to give the titlecompound (1.00 g) as a white powder.

[1110]¹H-NMR(DMSO-d₆)δ2.26-2.40(1H,m), 2.93-3.18(3H,m), 3.2-4.8(16H,m),7.09(1H,dd,J=7.7,4.8), 8.19(1H,dd,J=7.7,1.9), 8.49(1H,dd,J=4.8,1.9),9.16(1H,brs), 11.02(1H,brs), 12.7(1H,brs).

Example 210

[1111] Synthesis of3-{(2S,4S)-4-[4-(3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1112] (1) Piperazine (20.0 g) was melted by heating at 140° C. and2,3-dichloropyridine (3.42 g) was added thereto. The mixture was stirredat 120° C. for 2 hr. Water was added to the reaction mixture and themixture was extracted with chloroform. The extract was washed withbrine, dried and concentrated under reduced pressure to give1-(3-chloro-2-pyridyl)piperazine (4.68 g) as a dark-brown oil.

[1113] (2) Using the above-mentioned compound (0.712 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.41 g) was obtained as a white solid.

[1114]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.84-1.99(1H,m),2.40-2.51(1H,m), 2.53-2.73(4H,m), 2.79-3.18(3H,m), 3.28-3.45(5H,m),3.58-4.12(3H,m), 4.38-4.78(3H,m), 6.84(1H,dd,J=7.7,4.7 Hz),7.58(1H,dd,J=7.7,1.5 Hz), 8.18(1H,dd,J=4.7,1.5 Hz).

[1115] (3) The above-mentioned compound (1.40 g) was dissolved inethanol (4 mL), and 4.1 mol/L hydrochloric acid-ethanol (4 mL) was addedthereto. The mixture was stirred at room temperature for 14 hr. Theprecipitated solid was collected by filtration to give the titlecompound (1.14 g) as a white powder.

[1116]¹H-NMR(DMSO-d₆)δ2.30-2.43(1H,m), 2.95-3.18(3H,m), 3.2-4.2(13H,m),4.45-4.80(3H,m), 7.12(1H,dd,J=7.8,4.7 Hz), 7.89(1H,dd,J=7.8,1.5 Hz),8.28(1H,dd,J=4.7,1.5 Hz), 9.16(1H,brs), 10.96(1H,brs), 12.55(1H,brs).

Example 211

[1117] Synthesis of3-{(2S,4S)-4-[4-(5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1118] (1) Ethyl 6-chloronicotinate (1.12 g) was dissolved in DMF (30mL), and 1-tert-butoxycarbonylpiperazine (1.24 g) and potassiumcarbonate (1.00 g) were added thereto. The mixture was stirred at 80° C.for 18 hr. Water (100 mL) was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was washedsuccessively with saturated aqueous sodium hydrogencarbonate solutionand brine and dried. The solvent was evaporated under reduced pressure.The residue was dissolved in dichloromethane (10 mL), andtrifluoroacetic acid (5 mL) was added thereto at room temperature. Themixture was stirred for 2 hr and the reaction mixture was concentratedunder reduced pressure. Water (50 mL) was added to the residue, and themixture was washed with diethyl ether. The aqueous layer was basifiedwith aqueous sodium hydrogen carbonate solution. The mixture wasextracted with chloroform. The extract was dried and the mixture wasconcentrated under reduced pressure to give1-(5-ethoxycarbonyl-2-pyridyl)piperazine (1.17 g) as an oil.

[1119] (2) Using the above-mentioned compound (1.17 g) and the titlecompound (1.47 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(2.07 g) as a white solid.

[1120] (3) Using the above-mentioned compound (1.06 g), and in the samemanner as in Example 133 (2), the title compound (1.06 g) was obtainedas a white powder.

[1121]¹H-NMR(500 MHz,DMSO-d₆)δ1.30(3H,t,J=7.1 Hz), 2.23-2.43(1H,m),2.92-4.90(19H,m), 4.28(2H,q,J=7.1 Hz), 7.05(1H,d,J=9.1 Hz),8.04(1H,dd,J=9.1,2.3 Hz), 8.69(1H,d,J=2.3 Hz), 9.13(1H,brs),10.91(1H,brs), 12.58(1H,brs).

Example 212

[1122] Synthesis of3-{(2S,4S)-4-[4-(5-carboxy-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1123] 6 mol/L Hydrochloric acid was added to3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride [product of Example 211 (2), 1.00 g] and the mixturewas refluxed for 2 hr. The solvent was evaporated under reducedpressure, and the residue was purified by HPLC. This was converted tohydrochloride with 4 mol/L hydrochloric acid-1,4-dioxane to give thetitle compound (158 mg) as a white powder.

[1124]¹H-NMR(500 MHz,DMSO-d₆)δ2.21-2.41(1H,m), 2.90-4.90(19H,m),7.04(1H,d,J=9.0 Hz), 8.03(1H,dd,J=9.0,2.2 Hz), 8.67(1H,d,J=2.2 Hz),9.12(1H,brs), 10.80(1H,brs), 12.50(1H,brs).

Example 213

[1125] Synthesis of3-{(2S,4S)-4-[4-(5-carbamoyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1126] (1) Using 6-chloronicotinamide (5.00 g) and piperazine (27.6 g),and by reaction in the same manner as in Example 196 (1) at 100° C.,1-(5-carbamoyl-2-pyridyl)piperazine (0.41 g) was obtained as a yellowpowder.

[1127] (2) Using the above-mentioned compound (370 mg) and the titlecompound (450 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carbamoyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(350 mg) was obtained as a white solid.

[1128] (3) Using the above-mentioned compound (347 mg), and in the samemanner as in Example 133 (2), the title compound (332 mg) was obtainedas a white powder.

[1129]¹H-NMR(500 MHz,DMSO-d₆)δ1.81-2.01(1H,m), 2.93-4.10(14H,m),4.28-4.75(5H,m), 7.08(1H,d,J=9.0 Hz), 7.26(1H,brs), 7.91(1H,brs),8.10(1H,dd,J=9.0,2.3 Hz), 8.66(1H,d,J=2.3 Hz), 9.12(1H,brs),10.87(1H,brs), 12.51(1H,brs).

Example 214

[1130] Synthesis of3-{(2S,4R)-4-[4-(5-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1131] (1) The title compound (1.74 g) of Reference Example 11 andtriethylamine (1.0 mL) were dissolved in dichloromethane (35 mL), andmethanesulfonyl chloride (0.49 mL) was added dropwise under ice-cooling.The mixture was stirred for 3 hr. Iced water was added to the reactionmixture and the mixture was extracted with dichloromethane. The extractwas washed with brine, dried and concentrated under reduced pressure togive3-{(2S,4S)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(2.03 g) as a pale-brown solid.

[1132] (2) The-above-mentioned compound (1.10 g) and1-(5-cyano-2-pyridyl)piperazine (1.12 g) were dissolved in1-methyl-2-pyrrolidone (20 mL), and the mixture was stirred at 90° C.for 12 hr. The reaction mixture was added to water and the mixture wasextracted with ethyl acetate. The extract was concentrated under reducedpressure and the residue was purified by column chromatography to give3-{(2S,4R)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(170 mg).

[1133]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 2.07-2.20(2H,m),2.45-2.65(4H,m), 3.00-3.40(4H,m), 3.57-3.79(5H,m), 3.81-4.00(2H,m),4.45-4.83(3H,m), 6.59(1H,d,J=9.3 Hz), 7.61(1H,dd,J=9.3,1.9 Hz),8.40(1H,d,J=1.9 Hz).

[1134] (3) The above-mentioned compound (150 mg) was suspended intetrahydrofuran (40 mL), and 4 mol/L hydrochloric acid-ethyl acetate (40mL) was added thereto. The mixture was stirred at 55° C. for 5 hr. Afterallowing to cool, the precipitated solid was collected by filtration togive the title compound (130 mg) as a white powder.

[1135]¹H-NMR(DMSO-d₆)δ2.26-2.45(1H,m), 2.80-3.00(1H,m), 3.01-3.27(3H,m),3.28-3.94(8H,m), 3.95-4.15(3H,m), 4.38-4.77(3H,m), 4.84-5.01(1H,m),7.12(1H,d,J=9.3 Hz), 8.00(1H,dd,J=9.3,2.1 Hz), 8.58(1H,d,J=2.1 Hz),9.22(1H,brs).

Example 215

[1136] Synthesis of3-{(2S,4S)-4-[4-(3-chloro-5-trifluoromethyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1137] (1) Piperazine (40 g) was melted by heating at 140° C. and2,3-dichloro-5-trifluoromethylpyridine (10 g) was added thereto. Themixture was stirred at 120° C. for 2 hr. Water was added to the reactionmixture and the mixture was extracted with chloroform. The extract waswashed with brine, dried and concentrated under reduced pressure to give1-(3-chloro-5-trifluoromethyl-2-pyridyl)piperazine (12.8 g) as a brownsolid.

[1138] (2) Using the above-mentioned compound (0.956 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chloro-5-trifluoromethyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.64 g) was obtained as a white solid.

[1139]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.83-1.98(1H,m),2.38-2.50(1H,m), 2.52-2.70(4H,m), 2.78-3.19(3H,m), 3.33(1H,t,J=10.1 Hz),3.47-4.13(7H,m), 4.37-4.81(3H,m), 7.75(1H,s), 8.38(1H,s).

[1140] (3) The above-mentioned compound (1.64 g) was dissolved inethanol (4 mL), and 4.1 mol/L hydrochloric acid-ethanol (4 mL) was addedthereto. The mixture was stirred at room temperature for 5 days. Theprecipitated solid was collected by filtration to give the titlecompound (1.20 g) as a white powder.

[1141]¹H-NMR(DMSO-d₆)δ2.30-2.47(1H,m), 2.92-4.2(16H,m), 4.45-4.78(3H,m),8.31(1H,d,J=1.9 Hz), 8.63(1H,d,J=1.9 Hz), 9.15(1H,brs), 10.77(1H,brs),12.6(1H,brs).

Example 216

[1142] Synthesis of3-{(2S,4S)-4-[4-(3-chloro-5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1143] (1) 5,6-Dichloronicotinic acid (4.90 g) was dissolved in ethanol(40 mL), and thionyl chloride (2.0 mL) was added thereto underice-cooling. The mixture was refluxed for 1.5 hr. The reaction mixturewas concentrated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give ethyl 5,6-dichloronicotinate (4.85 g) as awhite solid.

[1144] (2) Piperazine (19.0 g) was melted by heating at 140° C. and theabove-mentioned compound (4.80 g) was added thereto. The mixture wasstirred at 120° C. for 2 hr. Water was added to the reaction mixture andthe mixture was extracted with chloroform. The extract was washed withbrine, dried and concentrated under reduced pressure to give1-(3-chloro-5-ethoxycarbonyl-2-pyridyl)piperazine (5.64 g) as a darkbrown solid.

[1145] (3) Using the above-mentioned compound (5.12 g) and the titlecompound (4.75 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chloro-5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(7.53 g) was obtained as a white solid.

[1146]¹H-NMR(CDCl₃)δ1.38(3H,t,J=7.1 Hz), 1.41(4.5H,s), 1.46(4.5H,s),1.83-1.98(1H,m), 2.38-2.50(1H,m), 2.53-2.73(4H,m), 2.78-3.20(3H,m),3.33(1H,t,J=10.3 Hz), 3.45-4.13(7H,m), 4.36(2H,q,J=7.1 Hz),4.32-4.78(3H,m), 8.11(1H,d,J=1.8 Hz), 8.74(1H,d,J=1.8 Hz).

[1147] (4) The above-mentioned compound (1.00 g) was dissolved indichloroethane (10 mL) and trifluoroacetic acid (5 mL) was addedthereto. The mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in ethyl acetate (10 mL). 4 mol/L Hydrochloricacid-ethyl acetate (2.25 mL) was added thereto, and the mixture wasstirred at room temperature for 1 hr. The precipitated solid wascollected by filtration to give the title compound (0.82 g) as a whitepowder.

[1148]¹H-NMR(DMSO-d₆)δ1.32(3H,t,J=7.1 Hz), 2.26-2.40(1H,m),2.93-3.18(3H,m), 3.25-4.15(13H,m), 4.32(2H,q,J=7.1 Hz), 4.4-4.78(3H,m),8.19(1H,d,J=2.0 Hz), 8.73(1H,d,J=2.0 Hz), 9.16(1H,brs), 10.78(1H,brs),12.5(1H,brs).

Example 217

[1149] Synthesis of3-{(2S,4S)-4-[4-(5-carboxy-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1150] (1)3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(3-chloro-5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 216 (3), 6.49 g] was dissolved in ethanol (30 mL),and aqueous solution (30 mL) of lithium hydroxide (0.59 g) was addedthereto. The mixture was stirred at room temperature for 19 hr andethanol was evaporated under reduced pressure. The concentrate waswashed with ethyl acetate, and 1 mol/L hydrochloric acid was addedthereto. The precipitated solid was collected by filtration to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carboxy-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(2.64 g) as a white solid.

[1151]¹H-NMR(DMSO-d₆)δ1.33(4.5H,s), 1.41(4.5H,s), 1.97-2.15(1H,m),2.77-2.87(1H,m), 2.95-4.25(15H,m), 4.40-4.76(3H,m), 8.16(1H,d,J=2.0 Hz),8.71(1H,d,J=2.0 Hz), 11.40(1H,brs).

[1152] (2) Using the above-mentioned compound (500 mg), and in the samemanner as in Example 216 (4), the title compound (437 mg) was obtainedas a white powder.

[1153]¹H-NMR(DMSO-d₆)δ2.27-2.42(1H,m), 2.94-3.18(3H,m), 3.2-4.8(16H,m),8.17(1H,d,J=2.0 Hz), 8.71(1H,d,J=2.0 Hz), 9.16(1H,brs), 10.95(1H,brs),12.60(1H,brs)

Example 218

[1154] Synthesis of3-{(2S,4S)-4-[4-(5-carbamoyl-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1155] (1)3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-carboxy-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 217 (1), 2.63 g] and ammonium chloride (0.54 g) weredissolved in DMF (30 mL), and N-methylmorpholine (1.1 mL), HOBT (1.53 g)and EDC hydrochloride (1.15 g) were successively added thereto. Themixture was stirred at room temperature for 4 hr. The reaction mixturewas concentrated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with ethyl acetate. The extract washed with brine and dried.The solvent was evaporated under reduced pressure to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carbamoyl-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(2.50 g) as a white solid.

[1156]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.45(4.5H,s), 1.84-1.98(1H,m),2.39-2.52(1H,m), 2.53-2.73(4H,m), 2.78-3.18(3H,m), 3.34(1H,t,J=10.0 Hz),3.45-4.13(7H,m), 4.38-4.78(3H,m), 5.87(1H,brs), 6.17(1H,brs),8.07(1H,d,J=2.0 Hz), 8.56(1H,d,J=2.0 Hz).

[1157] (2) The above-mentioned compound (683 mg) was dissolved inethanol (2 mL), and 4.1 mol/L hydrochloric acid-ethanol (2 mL) as addedthereto. The mixture was stirred at room temperature for 22 hr. Theprecipitated solid was collected by filtration to give the titlecompound (616 mg) as a white powder.

[1158]¹H-NMR(DMSO-d₆)δ2.26-2.42(1H,m), 2.92-4.3(16H,m), 4.46-4.78(3H,m),7.56(1H,brs), 8.12(1H,brs), 8.26(1H,s), 8.73(1H,s), 9.15(1H,brs),10.83(1H,brs), 12.52(1H,brs).

Example 219

[1159] Synthesis of3-{(2S,4S)-4-[4-(3-chloro-5-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1160] (1)3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-carbamoyl-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 218 (1), 1000 mg] and imidazole (195 mg) weredissolved in pyridine (10 mL), and phosphorus oxychloride (0.35 mL) wasadded thereto under ice-cooling. The mixture was stirred at roomtemperature for 13 hr and saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture. The mixture was extractedwith chloroform. The extract was washed with brine, dried andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-chloro-5-cyano-2-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(628 mg) as a white solid.

[1161]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.45(4.5H,s), 1.83-1.98(1H,m),2.38-2.70(5H,m), 2.80-3.20(3H,m), 3.33(1H,t,J=10.0 Hz), 3.53-4.13(7H,m),4.37-4.82(3H,m), 7.73(1H,d,J=1.9 Hz), 8.37(1H,d,J=1.9 Hz).

[1162] (2) The above-mentioned compound (622 mg) was dissolved in ethylacetate (1.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (1.5 mL)was added thereto. The mixture was stirred at room temperature for 14hr. The reaction mixture was concentrated under reduced pressure, andsaturated aqueous sodium hydrogencarbonate solution was added to theresidue. The mixture was extracted with chloroform. The extract wasdried and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to give a white solid. This was dissolvedin ethyl acetate (6 mL) and 4 mol/L hydrochloric acid-ethyl acetate (0.9mL) was added thereto. The mixture was stirred at room temperature for 1hr. The precipitated solid was collected by filtration to give the titlecompound (388 mg) as a white powder.

[1163]¹H-NMR(DMSO-d₆)δ2.10-2.26(1H,m), 2.90-4.2(16H,m), 4.47-4.78(3H,m),8.41(1H,d,J=1.9 Hz), 8.69(1H,d,J=1.9 Hz), 9.13(1H,brs), 10.81(1H,brs),12.57(1H,brs).

Example 220

[1164] Synthesis of3-{(2S,4S)-4-[4-(3,5-dichloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1165] (1) Piperazine (24.0 g) was melted by heating at 140° C. and2,3,5-trichloropyridine (5.00 g) was added thereto. The mixture wasstirred at 120° C. for 2 hr. Water was added to the reaction mixture andthe mixture was extracted with chloroform. The extract was washed withbrine, dried and concentrated under reduced pressure to give1-(3,5-dichloro-2-pyridyl)piperazine (6.43 g) as a brown solid.

[1166] (2) Using the above-mentioned compound (0.832 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,5-dichloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.35 g) was obtained as a white solid.

[1167]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.82-1.98(1H,m),2.38-2.50(1H,m), 2.53-2.73(4H,m), 2.78-3.22(3H,m), 3.28-3.44(5H,m),3.62-4.14(3H,m), 4.38-4.80(3H,m), 7.59(1H,d,J=2.2 Hz), 8.12(1H,d,J=2.2Hz).

[1168] (3) The above-mentioned compound (1.34 g) was dissolved inethanol (3.5 mL), and 4.1 mol/L hydrochloric acid-ethanol (3.5 mL) wasadded thereto. The mixture was stirred at room temperature for 15 hr.The precipitated solid was collected by filtration to give the titlecompound (1.10 g) as a white powder.

[1169]¹H-NMR(DMSO-d₆)δ2.20-2.38(1H,m), 2.90-4.15(16H,m),4.46-4.78(3H,m), 8.15(1H,d,J=2.3 Hz), 8.73(1H,d,J=2.3 Hz), 9.13(1H,brs),10.84(1H,brs), 12.55(1H,brs).

Example 221

[1170] Synthesis of3-{(2S,4S)-4-[4-(3,5-dichloro-4-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1171] (1) Using 1-(3,5-dichloro-4-pyridyl)piperazine (0.766 g) and thetitle compound (0.901 g) of Reference Example 12, and in the same manneras-in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3,5-dichloro-4-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.53 g) was obtained as a white solid.

[1172]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.82-1.98(1H,m),2.40-2.52(1H,m), 2.55-2.72(4H,m), 2.83-3.21(3H,m), 3.28-3.45(5H,m),3.62-4.14(3H,m), 4.38-4.81(3H,m), 8.33(2H,s).

[1173] (2) The above-mentioned compound (1.53 g) was dissolved in ethylacetate (7.5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (7.5 mL)was added thereto. The mixture was stirred at room temperature for 13hr. The precipitated solid was collected by filtration to give the titlecompound (1.64 g) as a white powder.

[1174]¹H-NMR(DMSO-d₆)δ2.27-2.43(1H,m), 2.95-4.2(16H,m), 4.45-4.78(3H,m),8.52(2H,s), 9.14(1H,brs), 10.97(1H,brs), 12.6(1H,brs).

Example 222

[1175] Synthesis of3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1176] (1) 1-tert-Butoxycarbonylpiperazine (5.02 g) was dissolved in DMF(90 mL), and diketene (2.50 mL) was added thereto at room temperature.The mixture was stirred for 1.5 hr and the solvent was evaporated underreduced pressure. Water was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with brine anddried. The solvent was evaporated under reduced pressure to give1-acetoacetyl-4-tert-butoxycarbonylpiperazine (6.26 g) as a pale-brownpowder.

[1177] (2) The above-mentioned compound (6.24 g) was dissolved inethanol (500 mL), and phenylhydrazine (2.27 mL) and methanesulfonic acid(350 μL) were added at room temperature. The mixture was stirred for 14hr and pyridine (6 mL) was added to the reaction mixture. The solventwas evaporated under reduced pressure and the residue was dissolved inpyridine (250 mL). Phosphorus oxychloride (5.0 mL) was added thereto atroom temperature and the mixture was stirred for 20 hr. The solvent wasevaporated under reduced pressure, the residue was acidified with dilutehydrochloric acid to pH 3. The mixture was extracted with ethyl acetate.The extract was washed successively with saturated aqueous sodiumhydrogencarbonate solution and brine and dried. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel chromatography to give1-tert-butoxycarbonyl-4-(3-methyl-1-phenyl-5-pyrazolyl)piperazine (935mg) as an oil.

[1178] (3) The above-mentioned compound (935 mg) was dissolved indichloromethane (10 mL), and trifluoroacetic acid (5 mL) was addedthereto at room temperature. The mixture was stirred for 1.5 hr. Thesolvent was evaporated under reduced pressure, and water (50 mL) wasadded to the residue. The mixture was washed with diethyl ether. Theaqueous layer was basified with aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with chloroform. The extract wasdried, and evaporated under reduced pressure to give1-(3-methyl-1-phenyl-5-pyrazolyl)piperazine (584 mg) as a brown powder.

[1179] (4) Using the above-mentioned compound (584 mg) and the titlecompound (604 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-methyl-1-phenyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(846 mg) was obtained as a pale-yellow powder.

[1180] (5) Using the above-mentioned compound (844 mg), and in the samemanner as in Example 133 (2), the title compound (751 mg) was obtainedas a white solid.

[1181]¹H-NMR(500 MHz,DMSO-d₆)δ2.17(3H,s), 2.18-2.38(1H,m),2.90-4.10(16H,m), 4.46-4.74(3H,m), 5.93(1H,s), 7.31(1H,m), 7.47(2H,m),7.79(2H,m), 9.09(1H,brs), 10.91(1H,brs), 12.40(1H,brs).

Example 223

[1182] Synthesis of3-{(2S,4S)-4-[4-(1-tert-butyl-3-methyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1183] (1) 1-Acetoacetyl-4-tert-butoxycarbonylpiperazine [product ofExample 222 (1), 3.92 g] was dissolved in ethanol (300 mL), andtert-butylhydrazine hydrochloride (1.81 g) and molecular sieves 3A (10g) were added thereto at room temperature. The mixture was stirred for15 hr. The reaction mixture was filtrated and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inpyridine (200 mL), and phosphorus oxychloride (3.0 mL) was added theretoat room temperature. The mixture was stirred for 24 hr. The reactionmixture was concentrated under reduced pressure, the residue wasacidified with dilute hydrochloric acid to pH 3. The mixture wasextracted with ethyl acetate. The extract was washed successively withsaturated aqueous sodium hydrogencarbonate solution and brine and dried.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel chromatography to give1-tert-butoxycarbonyl-4-(1-tert-butyl-3-methyl-5-pyrazolyl)piperazine(886 mg) as an oil.

[1184] (2) Using the above-mentioned compound (880 mg), and in the samemanner as in Example 222 (3),1-(3-methyl-1-tert-butyl-5-pyrazolyl)piperazine (607 mg) was obtained asa pale-yellow powder.

[1185] (3) Using the above-mentioned compound (0.607 g) and the titlecompound (0.781 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-methyl-1-tert-butyl-5-pyrazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.17 g) was obtained as a white powder.

[1186] (4) Using the above-mentioned compound (1.17 g), and in the samemanner as in Example 133 (2), the title compound (0.902 g) was obtainedas a white solid.

[1187]¹H-NMR(500 MHz,DMSO-d₆)δ1.56(9H,s), 2.09(3H,s), 2.27-2.47(1H,m),2.90-4.20(16H,m), 4.48-4.78(3H,m), 6.00(1H,s), 9.12(1H,brs),11.12(1H,brs), 12.49(1H,brs).

Example 224

[1188] Synthesis of3-{(2S,4S)-4-[4-(1-phenyl-2-imidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1189] (1) 1-Benzyloxycarbonylpiperazine (5.00 g) was dissolved inacetone (50 mL), and phenyl isothiocyanate (2.9 mL) was added theretounder ice-cooling. The mixture was stirred at room temperature for 1 hr.The precipitated solid was collected by filtration to give1-(anilinocarbothioyl)-4-(benzyloxycarbonyl)piperazine (5.08 g) as awhite powder.

[1190] (2) The above-mentioned compound (5.07 g) was dissolved inmethanol (100 mL) and dichloromethane (20 mL), methyl iodide (1.4 mL)were added thereto. The mixture was stirred at room temperature for 17hr. The reaction mixture was concentrated under reduced pressure, andsaturated aqueous sodium hydrogencarbonate solution was added to theresidue. The mixture was extracted with dichloromethane, and the extractwas washed with brine, dried and concentrated under reduced pressure togive 1-benzyloxycarbonyl-4-[(methylthio)phenyliminomethyl]piperazine(5.71 g) as a slightly yellow oil.

[1191] (3) The above-mentioned compound (3.00 g) and aminoacetaldehydedimethyl acetal (1.8 mL) were dissolved in pyridine (15 mL), and themixture was stirred at 100° C. for 2 days with heating. The reactionmixture was concentrated under reduced pressure, and saturated aqueoussodium hydrogencarbonate solution was added to the residue. The mixturewas extracted with chloroform and the extract was washed with brine,dried and concentrated under reduced pressure. The residue was dissolvedin 2 mol/L hydrochloric acid (30 mL), and heated at 100° C. for 2 hr.Saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture, and the mixture was extracted with chloroform. Theextract was washed with brine, dried and concentrated under reducedpressure. The residue was purified by silica gel chromatography to give1-benzyloxycarbonyl-4-(1-phenyl-2-imidazolyl)piperazine (1.16 g) as abrown oil.

[1192] (4) The above-mentioned compound (1.16 g) was dissolved inmethanol (30 mL). The solution was stirred in the presence of 10%palladium/carbon (232 mg) under a hydrogen atomosphere (1 atm) at roomtemperature for 20 hr. The reaction mixture was filtrated and thefiltrate was concentrated under reduced pressure to give1-(1-phenyl-2-imidazolyl)piperazine (0.742 g) as a white solid.

[1193] (5) Using the above-mentioned compound (0.740 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-phenyl-2-imidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.30 g) was obtained as a white solid.

[1194]¹H-NMR(CDCl₃)δ1.39(4.5H,s), 1.44(4.5H,s), 1.75-1.92(1H,m),2.36-2.57(5H,m), 2.74-2.89(1H,m), 2.93-3.17(6H,m), 3.25(1H,t,J=10.0 Hz),3.60-4.08(3H,m), 4.34-4.77(3H,m), 6.83-6.88(2H,m), 7.34(1H,t,J=7.1 Hz),7.43-7.54(4H,m).

[1195] (6) The above-mentioned compound (1.30 g) was dissolved inethanol (3 mL), and 4.1 mol/L hydrochloric acid-ethanol (3 mL) was addedthereto. The mixture was stirred at room temperature for 18 hr. Theprecipitated solid was collected by filtration to give the titlecompound (1.15 g) as a white powder.

[1196]¹H-NMR(DMSO-d₆)δ2.10-2.26(1H,m), 2.83-4.05(16H,m),4.43-4.77(3H,m), 7.48(1H,d,J=2.3 Hz), 7.53(1H,d,J=2.3 Hz),7.54-7.72(5H,m), 9.07(1H,brs), 10.98(1H,brs).

Example 225

[1197] Synthesis of3-{(2S,4S)-4-[4-(5-methyl-1-phenyl-2-imidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1198] (1)1-Benzyloxycarbonyl-4-[(methylthio)phenyliminomethyl]piperazine [productof Example 224 (2), 2.70 g] and propargylamine (2.3 mL) were dissolvedin 1-butanol (25 mL), and p-toluenesulfonic acid monohydrate (156 mg)was added thereto. The mixture was refluxed for 20 hr. The reactionmixture was concentrated under reduced pressure, and saturated aqueoussodium hydrogencarbonate solution was added to the residue. The mixturewas extracted with chloroform, and the extract was washed with brine,dried and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography to give1-benzyloxycarbonyl-4-(5-methyl-1-phenyl-2-imidazolyl)piperazine (1.82g) as a brown oil.

[1199] (2) Using the above-mentioned compound (1.16 g), and in the samemanner as in Example 224 (4),1-(5-methyl-1-phenyl-2-imidazolyl)piperazine (1.23 g) was obtained as abrown solid.

[1200] (3) Using the above-mentioned compound (0.800 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methyl-1-phenyl-2-imidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.20 g) was obtained as a white solid.

[1201]¹H-NMR(CDCl₃)δ1.38(4.5H,s), 1.43(4.5H,s), 1.75-1.88(1H,m),1.99(3H,s), 2.28-2.46(5H,m), 2.68-2.83(1H,m), 2.90-3.16(6H,m),3.22(1H,t,J=10.1 Hz), 3.57-4.07(3H,m), 4.32-4.75(3H,m), 6.57(1H,s),7.27-7.53(5H,m).

[1202] (4) The above-mentioned compound (1.19 g) was dissolved inethanol (3 mL), and 4.1 mol/L hydrochloric acid-ethanol (3 mL) as addedthereto. The mixture was stirred at room temperature or 13 hr. Theprecipitated solid was collected by filtration to give the titlecompound (0.913 g) as a white powder.

[1203]¹H-NMR(DMSO-d₆)δ2.00-2.18(1H,m), 2.79-3.93(16H,m),4.42-4.76(3H,m), 7.23(1H,s), 7.58-7.72(5H,m), 9.02(1H,brs),10.86(1H,brs), 14.01(1H,brs).

Example 226

[1204] Synthesis of3-{(2S,4S)-4-[4-(4-phenyl-2-thiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1205] (1) Phenacyl bromide (4 g) was dissolved in acetonitrile (30 mL),and sodium thiocyanate (1.8 g) was added at room temperature withstirring. The reaction mixture was concentrated under reduced pressure,and brine was added to the residue. The mixture was extracted with ethylacetate. The extract was dried, and the solvent was evaporated underreduced pressure to give 2-isocyanatoacetophenone (3.53 g) as whitecrystals.

[1206] (2) Piperazine (3.8 g) was dissolved in ethanol (40 mL), and asolution of the above-mentioned compound (3.53 g) in ethyl acetate (10mL) was added thereto. The mixture was heated at 70° C. for 1 hr. Thereaction mixture was concentrated under reduced pressure, and brine wasadded to the residue. The mixture was extracted with ethyl acetate, andthe extract was dried and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to give4-phenyl-2-(1-piperazinyl)thiazole (2.38 g) as a yellow oil.

[1207] (3) Using the above-mentioned compound (0.810 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-phenyl-2-thiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.59 g) was obtained as a pale-yellow solid.

[1208]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.84-1.98(1H,m),2.40-2.72(5H,m), 2.80-3.18(3H,m), 3.34(1H,t,J=9.9 Hz), 3.49-4.15(7H,m),4.38-4.80(3H,m), 6.78(1H,s), 7.26-7.46(13H,m), 7.83(2H,d,J=7.1 Hz).

[1209] (4) The above-mentioned compound (1.59 g) was dissolved inethanol (6 mL), and 4.1 mol/L hydrochloric acid-ethanol (6 mL) was addedthereto. The mixture was stirred at room temperature for 12 hr. Theprecipitated solid was collected by filtration to give the titlecompound (1.41 g) as a pale-brown powder.

[1210]¹H-NMR(DMSO-d₆)δ2.27-2.42(1H,m), 2.95-3.18(3H,m),3.37-4.18(16H,m), 4.47-4.78(3H,m), 7.30(1H,t,J=7.3 Hz), 7.37-7.45(3H,s),7.87(2H,d,J=7.1 Hz), 9.17(1H,brs), 10.93(1H,brs).

Example 227

[1211] Synthesis of3-((2S,4S)-4-{4-[4-(4-cyanophenyl)-2-thiazolyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinetrihydrochloride

[1212] (1) 4-Acetylbenzonitrile (4.35 g) was dissolved in chloroform (40mL), and a solution of bromine (1.7 mL) in chloroform (10 mL) was addeddropwise. The mixture was stirred at room temperature. The reactionmixture was washed with saturated aqueous sodium hydrogencarbonatesolution, dried and concentrated under reduced pressure. The residue wasdissolved in acetonitrile (40 mL), and sodium thiocyanate (2.4 g) wasadded thereto. The mixture was stirred at room temperature andconcentrated under reduced pressure. Brine was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was dried andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography to give4-(2-isocyanatoacetyl)benzonitrile (4.39 g) as yellow crystals.

[1213] (2) The above-mentioned compound (4.39 g) and piperazine (4.15 g)were dissolved in ethanol (70 mL), and the mixture was stirred at 80° C.for 1 hr with heating. The reaction mixture as concentrated underreduced pressure, and brine was added to the residue. The mixture wasextracted with ethyl acetate. The extract was dried and concentratedunder reduced pressure. The residue was purified by silica gelchromatography to give 1-[4-(4-cyanophenyl)-2-thiazolyl]piperazine (1.83g) as a yellow solid.

[1214] (3) Using the above-mentioned compound (0.892 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[4-(4-cyanophenyl)-2-thiazolyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(1.40 g) was obtained as a brown solid.

[1215]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.83-1.98(1H,m),2.38-2.75(5H,m), 2.82-3.22(3H,m), 3.34(1H,t,J=9.9 Hz), 3.48-4.15(7H,m),4.38-4.81(3H,m), 6.93(1H,s), 7.65(2H,d,J=8.3 Hz), 8.34(2H,d,J=8.3 Hz).

[1216] (4) The above-mentioned compound (1.39 g) was dissolved in ethylacetate (3 mL), and 4 mol/L hydrochloric acid-ethyl acetate (6 mL) wasadded thereto. The mixture was stirred at room temperature for 4 days.The precipitated solid was collected by filtration to give the titlecompound (1.23 g) as a pale-yellow powder.

[1217]¹H-NMR(DMSO-d₆)δ2.24-2.38(1H,m), 2.94-3.18(3H,m),3.35-4.14(16H,m), 4.46-4.78(3H,m), 7.73(1H,s), 7.87(2H,d,J=8.5 Hz),8.07(2H,d,J=8.5 Hz), 9.16(1H,brs), 10.83(1H,brs).

Example 228

[1218] Synthesis of3-{(2S,4S)-4-[4-(1-phenyl-1H-tetrazol-5-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1219] (1) Using 5-chloro-1-phenyl-1H-tetrazol (2.10 g) and piperazine(10.0 g), and reaction at 100° C. in the same manner as in Example 196(1), 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (2.67 g) was obtained as apale-yellow powder.

[1220] (2) Using the above-mentioned compound (0.59 g) and the titlecompound (0.696 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-phenyl-1H-tetrazol-5-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.19 g) was obtained as a white powder.

[1221] (3) Using the above-mentioned compound (1.19 g), and in the samemanner as in Example 133 (2), the title compound (0.863 g) was obtainedas a white powder.

[1222]¹H-NMR(500 MHz,DMSO-d₆)δ2.02-2.22(1H,m), 2.80-3.95(16H,m),4.45-4.73(3H,m), 7.57-7.73(5H,m), 9.04(1H,brs), 10.61(1H,brs).

Example 229

[1223] Synthesis of3-{(2S,4S)-4-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1224] (1) 1-Benzyloxycarbonylpiperazine (2.07 g) was dissolved indichloromethane (50 mL), and cyclohexyl isocyanate (1.20 mL) was addedthereto at room temperature. The mixture was stirred for 1 hr. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in tetrahydrofuran (100 mL). Phosphorus oxychloride (8.8 mL)was added thereto, and the mixture was refluxed for 18 hr. The reactionmixture was concentrated under reduced pressure, and a 0.5 mol/Lsolution of triazole in acetonitrile (100 mL) was added to the residue.The mixture was stirred at room temperature for 3 hr. The solvent wasevaporated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with ethyl acetate, and the extract was washed with brine anddried. The solvent was distilled away under reduced pressure, and theresidue was dissolved in methanol (100 mL). An aqueous solution (20 mL)of sodium azide (6.50 g) was added thereto. The mixture was stirred at70° C. for 3 hr and the reaction mixture was concentrated under reducedpressure. Water was added to the residue, and the mixture was extractedwith ethyl acetate. The extract was washed with brine and dried. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel chromatography to give1-benzyloxycarbonyl-4-(1-cyclohexyl-1H-tetrazol-5-yl)piperazine (390 mg)as a white powder.

[1225] (2) The above-mentioned compound (388 mg) was dissolved inethanol (10 mL) and ethyl acetate (10 mL). The mixture was stirred inthe presence of 10% palladium/carbon (140 mg) under a hydrogenatomosphere (1 atm) for 2 hr. The reaction mixture was filtrated and thefiltrate was concentrated under reduced pressure to give1-(1-cyclohexyl-1H-tetrazol-5-yl)piperazine (248 mg) as a white powder.

[1226] (3) Using the above-mentioned compound (248 mg) and the titlecompound (290 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(502 mg) was obtained as a white powder.

[1227] (4) Using the above-mentioned compound (502 mg), and in the samemanner as in Example 133 (2), the title compound (302 mg) was obtainedas a white powder.

[1228]¹H-NMR(500 MHz,DMSO-d₆)δ1.20-1.34(1H,m), 1.40-1.50(2H,m),1.64-1.88(5H,m), 1.97-2.03(2H,m), 2.12-2.32(1H,m), 2.90-4.05(16H,m),4.25(1H,m), 4.48-4.75(3H,m), 9.10(1H,brs), 10.67(1H,brs).

Example 230

[1229] Synthesis of3-{(2S,4S)-4-[4-(2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1230] (1) Using 2-chlorobenzimidazole (0.500 g) and piperazine (8.47g), and in the same manner as in Example 189 (1),1-(2-benzimidazolyl)piperazine (0.086 g) was obtained as a white powder.

[1231] (2) Using the above-mentioned compound (86 mg) of ReferenceExample 12 and the title compound (128 mg), and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(2-benzimidazolyl)-1-piperazinyl]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(203 mg) was obtained as a white solid.

[1232] (3) Using the above-mentioned compound (203 mg), and in the samemanner as in Example 186 (2), the title compound (94 mg) was obtained asa white powder.

[1233]¹H-NMR(DMSO-d₆)δ1.72-2.16(1H,m), 2.65-4.30(16H,m),4.40-4.80(3H,m), 7.18-7.33(2H,m), 7.36-7.51(2H,m), 8.95(1H,brs),9.70(1H,brs), 10.50(1H,brs), 13.71(2H,brs).

Example 231

[1234] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1235] (1) 4-Amino-3-nitrobenzonitrile (25 g) was dissolved in methanol(200 mL) and tetrahydrofuran (200 mL). The mixture was stirred in thepresence of 10% palladium/carbon (3.0 g) under a hydrogen atomosphere (1atm) for 20 hr. The reaction mixture was filtrated and the filtrate wasconcentrated under reduced pressure to give 3,4-diaminobenzonitrile (20g) as a charcoal brown solid.

[1236] (2) The above-mentioned compound (2.60 g) was dissolved in DMF(20 mL) and pyridine (2 mL), and a solution of triphosgene (2.12 g) intetrahydrofuran (20 mL) was added dropwise under ice-cooling. Themixture was stirred at room temperature for 18 hr. Dilute hydrochloricacid was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The extract was washed with brine and dried. Thesolvent was evaporated under reduced pressure and ethyl acetate wasadded to the residue. The precipitated solid was collected by filtrationto give 2-hydroxybenzimidazole-5-carbonitrile (896 g) as a purple solid.

[1237] (3) The above-mentioned compound (894 mg) was dissolved inphosphorus oxychloride (12 mL), and the solution was refluxed for 3 hr.The reaction mixture was added to ice, and extracted with ethyl acetate.The extract was washed with brine, dried and concentrated under reducedpressure. The residue was purified by silica gel chromatography to give2-chlorobenzimidazole-5-carbonitrile (322 mg) as a white powder.

[1238] (4) The product (345 mg) of Example 199 (3) was dissolved inN-methyl-2-pyrrolidone (6 mL), and the above-mentioned compound (182 mg)and N,N-diisopropylethylamine (180 μL) were added thereto. The mixturewas stirred at 100° C. for 17 hr. The reaction mixture was added towater, and the mixture was extracted with ethyl acetate. The extract waswashed with brine, dried and concentrated under reduced pressure. Theresidue was purified by HPLC to give3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(5-cyano-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(250 mg) as a white solid.

[1239] (5) Using the above-mentioned compound (200 mg), and in the samemanner as in Example 199 (5), the title compound (50 mg) was obtained asa white powder.

[1240]¹H-NMR(500 MHz,DMSO-d₆)δ1.89-2.09(1H,m), 2.78-4.20(16H,m),4.47-4.82(3H,m), 7.51(1H,d,J=8.2 Hz), 7.61(1H,d,J=8.2 Hz), 7.81(1H,s),8.97(1H,brs), 10.28(1H,brs).

Example 232

[1241] Synthesis of3-{(2s,4s)-4-[4-(5-trifluoromethyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrobromide

[1242] (1) Using 4-trifluoromethyl-2-nitroaniline (25.0 g), and in thesame manner as in Example 231 (1),4-trifluoromethyl-1,2-phenylenediamine (21.3 g) was obtained as a whitesolid.

[1243] (2) Using the above-mentioned compound (10.2 g) and in the samemanner as in Example 231 (2), the reaction mixture was added to water.The precipitated solid was collected by filtration to give5-trifluoromethyl-2-hydroxybenzimidazole (3.28 g) as a white solid.

[1244] (3) Using the above-mentioned compound (3.27 g), and in the samemanner as in Example 231 (3), 2-chloro-5-trifluoromethylbenzimidazole(2.48 g) was obtained as a white powder.

[1245] (4) Using the above-mentioned compound (226 mg) and the product(345 mg) of Example 199 (3), and in the same manner as in Example 231(4),3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(5-trifluoromethyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(192 mg) was obtained as a white solid.

[1246] (5) 30% Hydrogen bromide-acetic acid solution (10 mL) was addedto the above-mentioned compound (190 mg), and the mixture was stirred atroom temperature for 6 hr. Diethyl ether was added to the reactionmixture, and the precipitated solid was collected by filtration andwashed with ethanol. The title compound (101 mg) was obtained as a whitepowder.

[1247]¹H-NMR(500 MHz,DMSO-d₆)δ1.761.96(1H,m), 2.75-4.80(16H,m),4.46-4.74(3H,m), 7.60(2H,s), 7.67(1H,s), 8.96(1H,brs), 9.59(1H,brs),13.02(1H,brs).

Example 233

[1248] Synthesis of3-{(2S,4S)-4-[4-(5-fluoro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrobromide

[1249] (1) Using 4-fluoro-2-nitroaniline (25.0 g), and in the samemanner as in Example 231 (1), 4-fluoro-1,2-phenylenediamine (20.1 g) wasobtained as a charcoal brown solid.

[1250] (2) Using the above-mentioned compound (10.0 g), and in the samemanner as in Example 231 (2), the reaction mixture was added to water.The precipitated solid was collected by filtration to give5-fluoro-2-hydroxybenzimidazole (2.14 g) as a brown solid.

[1251] (3) Using the above-mentioned compound (2.13 g), and in the samemanner as in Example 231 (3), 2-chloro-5-fluorobenzimidazole (1.44 g)was obtained as a brown solid.

[1252] (4) Using the above-mentioned compound (174 mg) and the product(345 mg) of Example 199 (3), and in the same manner as in Example 231(4),3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(5-fluoro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(66 mg) was obtained as a white solid.

[1253] (5) Using the above-mentioned compound (66 mg), and in the samemanner as in Example 232 (5), the title compound (20 mg) was obtained asa white powder.

[1254]¹H-NMR(500 MHz,DMSO-d₆)δ1.77-1.97(1H,m), 2.88-4.20(16H,m),4.46-4.76(3H,m), 7.12-7.16(1H,m), 7.32(1H,dd,J=8.5,2.2 Hz),7.44(1H,dd,J=8.7,4.5 Hz), 8.97(1H,brs), 9.61(1H,brs), 13.16(1H,brs).

Example 234

[1255] Synthesis of3-{(2S,4S)-4-[4-(5-chloro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrobromide

[1256] (1) 2-Chlorobenzimidazole (1.05 g) was dissolved in DMF (10 mL),and N-chlorosuccinimide (1.01 g) was added thereto. The mixture wasstirred at 60° C. for 30 min and the reaction mixture was added towater. The precipitated solid was collected by filtration to give2,5-dichlorobenzimidazole (0.480 g) as a white solid.

[1257] (2) Using the above-mentioned compound (191 mg) and the product(345 mg) of Example 199 (3), and in the same manner as in Example 231(4),3-{(2S,4S)-1-benzyloxycarbonyl-4-[4-(5-chloro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(122 mg) was obtained as a pale-yellow solid.

[1258] (3) Using the above-mentioned compound (110 mg), and in the samemanner as in Example 232 (5), the title compound (56 mg) was obtained asa white powder.

[1259]¹H-NMR(500 MHz,DMSO-d₆)δ1.76-1.96(1H,m), 2.70-4.87(16H,m),4.46-4.74(3H,m), 7.32(1H,dd,J=8.5,1.7 Hz), 7.44(1H,d,J=8.5 Hz),7.48(1H,d,J=1.7 Hz), 8.96(1H,brs), 9.59(1H,brs), 13.15(1H,brs).

Example 235

[1260] Synthesis of3-{(2S,4S)-4-[4-(5-nitro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1261] (1) Using 4-nitro-1,2-phenylenediamine (9.12 g), and in the samemanner as in Example 231 (2), the reaction mixture was added to water.The precipitated solid was collected by filtration to give5-nitro-2-hydroxyxisobenzimidazole (5.69 g) as an yellow solid.

[1262] (2) Using the above-mentioned compound (5.69 g), and in the samemanner as in Example 231 (3), 2-chloro-5-nitrobenzimidazole (2.41 g) wasobtained as a yellow solid.

[1263] (3) Using the above-mentioned compound (1.00 g) and piperazine(4.70 g), and by a reaction at 100° C. in the same manner as in Example196 (1), 1-(5-nitro-2-benzimidazolyl)piperazine (0.16 g) was obtained asan orange solid.

[1264] (4) Using the above-mentioned compound (160 mg) and the titlecompound (162 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-nitro-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(172 mg) was obtained as a yellow solid.

[1265] (5) Using the above-mentioned compound (172 mg), and in the samemanner as in Example 133 (2), the title compound (138 mg) was obtainedas a yellow powder.

[1266]¹H-NMR(500 MHz,DMSO-d₆)δ2.08-2.24(1H,m), 2.78-4.03(16H,m),4.48-4.75(3H,m), 7.52(2H,d,J=8.6 Hz), 8.11(2H,dd,J=8.6,2.0 Hz),8.12(1H,d,J=2.0 Hz), 9.06(1H,brs), 10.59(1H,brs).

Example 236

[1267] Synthesis of3-{(2S,4S)-4-[4-(1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1268] (1) Sodium hydride (contained by 60%, 0.288 g) was suspended inDMF (10 mL), and 2-chlorobenzimidazole (1 g) was added thereto. Themixture was stirred at room temperature for 30 min and methyl iodide(0.61 mL) was added thereto. After stirring at room temperature for 1hr, water was added to the reaction mixture. The mixture was extractedwith ethyl acetate, and the extract was washed with brine andconcentrated under reduced pressure to give2-chloro-1-methylbenzimidazole (0.928 g) as a white powder.

[1269] (2) Using the above-mentioned compound (0.928 g) and piperazine(9.60 g), and in the same manner as in Example 189 (1),1-(1-methyl-2-benzimidazolyl)piperazine (1.18 g) was obtained as apale-yellow solid.

[1270] (3) Using the above-mentioned compound (476 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(947 mg) was obtained as a white solid.

[1271] (4) Using the above-mentioned compound (857 mg), and in the samemanner as in Example 186 (2), the title compound (532 mg) was obtainedas a white powder.

[1272]¹H-NMR(DMSO-d₆)δ2.19-2.38(1H,m), 2.89-3.20(3H,m),3.30-4.30(13H,m), 3.79(3H,s), 4.42-4.85(3H,m), 7.34-7.47(2H,m),7.53-7.63(1H,m), 7.64-7.76(1H,m), 9.15(1H,brs), 11.08(1H,brs).

Example 237

[1273] Synthesis of3-{(2S,4S)-4-[4-(5-trifluoromethyl-1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1274] (1) 4-Fluoro-3-nitrobenzotrifluoride (25 g) was dissolved inethanol (50 mL), and 30% methylamine-ethanol solution (97.9 g) wasgradually added dropwise under ice-cooling, and the mixture was stirredat room temperature for 40 min. The reaction mixture was added to water,and the precipitated solid was collected by filtration to give4-methylamino-3-nitrobenzotrifluoride (25.5 g) as yellow crystals.

[1275] (2) Using the above-mentioned compound (25.3 g), and in the samemanner as in Example 231 (1),4-trifluoromethyl-N1-methyl-1,2-phenylenediamine (21.9 g) was obtainedas a pale-yellow solid.

[1276] (3) The above-mentioned compound (21.9 g) was subjected to thereaction in the same manner as in Example 231 (2), and water was addedto the reaction mixture. The precipitated solid was collected byfiltration to give 5-trifluoromethyl-2-hydroxy-1-methylbenzimidazole(23.8 g) as a white solid.

[1277] (4) Using the above-mentioned compound (10.1 g), and in the samemanner as in Example 231 (3),2-chloro-5-trifluoromethyl-1-methylbenzimidazole (10.5 g) was obtainedas a white solid.

[1278] (5) Using the above-mentioned compound (5.07 g) and piperazine(18.6 g), and by a reaction at 100° C. in the same manner as in Example196 (1), 1-(5-trifluoromethyl-1-methyl-2-benzimidazolyl)piperazine (4.87g) was obtained as a white solid.

[1279] (6) Using the above-mentioned compound (485 mg) and the titlecompound (518 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-trifluoromethyl-1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(978 mg) was obtained as a white powder.

[1280] (7) Using the above-mentioned compound (978 mg), and in the samemanner as in Example 133 (2), the title compound (483 mg) was obtainedas a white powder.

[1281]¹H-NMR(500 MHz,DMSO-d₆)δ2.23-2.43(1H,m), 2.97-4.15(16H,m),3.76(3H,s), 4.49-4.77(3H,m), 7.61(1H,d,J=8.4 Hz), 7.74(1H,d,J=8.4 Hz),7.80(1H,s), 9.14(1H,brs), 10.94(1H,brs).

Example 238

[1282] Synthesis of3-{(2S,4S)-4-[4-(5-fluoro-1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1283] (1) Using 2,5-difluoronitrobenzene (25.4 g), and in the samemanner as in Example 237 (1), 5-fluoro-2-(methylamino)nitrobenzene (27.2g) was obtained as an orange solid.

[1284] (2) Using the above-mentioned compound (27.2 g), and in the samemanner as in Example 231 (1), 4-fluoro-N1-methyl-1,2-phenylenediamine(20.9 g) was obtained as an orange solid.

[1285] (3) Using the above-mentioned compound (18.1 g), and in the samemanner as in Example 231 (2), 5-fluoro-2-hydroxy-1-methylbenzimidazole(0.682 g) was obtained as a pale-yellow solid.

[1286] (4) Using the above-mentioned compound (675 mg), and in the samemanner as in Example 231 (3), 2-chloro-5-fluoro-1-methylbenzimidazole(647 mg) was obtained as a white solid.

[1287] (5) Using the above-mentioned compound (0.633 g) and piperazine(3.2 g), and by a reaction at 100° C. in the same manner as in Example196 (1), 1-(5-fluoro-1-methyl-2-benzimidazolyl)piperazine (0.77 g) wasobtained as a pale-yellow solid.

[1288] (6) Using the above-mentioned compound (0.76 g) and the titlecompound (0.80 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-fluoro-1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.40 g) was obtained as a white powder.

[1289] (7) Using the above-mentioned compound (1.40 g), and in the samemanner as in Example 133 (2), the title compound (0.676 g) was obtainedas a white powder.

[1290]¹H-NMR(500 MHz,DMSO-d₆)δ2.20-2.40(1H,m), 2.85-4.14(16H,m),3.76(3H,s), 4.49-4.76(3H,m), 7.23(1H,m), 7.38(1H,dd,J=8.6,2.1 Hz),7.65(1H,dd,J=8.7,4.3 Hz), 9.13(1H,brs), 11.03(1H,brs).

Example 239

[1291] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-benzoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1292] (1) 3-Amino-4-cyanophenol (6.71 g) was dissolved in pyridine (100mL), and potassium ethylxanthate (8.82 g) was added thereto. The mixturewas refluxed for 2 hr. After allowing to cool, iced water (200 mL) wasadded to the reaction mixture, and conc. hydrochloric acid (40 mL) wasadded thereto. The precipitated solid was collected by filtration togive 5-cyano-2-mescaptobenzoxazole (5.62 g) as a gray powder.

[1293] (2) The above-mentioned compound (5 g) and two drops of DMF wereadded to thionyl chloride (20 mL), and the mixture was refluxed for 1hr. The reaction mixture was concentrated under reduced pressure to give2-chloro-5-cyanobenzoxazole (5.06 g).

[1294] (3) Piperazine (4.29 g) was dissolved in DMF (40 mL), and theabove-mentioned compound (2.96 g) was added thereto. The mixture wasstirred at room temperature for 3 hr. The reaction mixture was added towater, and the mixture was extracted with chloroform. 1 mol/LHydrochloric acid was added to the extract, and the aqueous layer wasseparated. Aqueous sodium hydroxide solution was added thereto, and themixture was extracted with chloroform. The extract was concentratedunder reduced pressure to give 1-(5-cyano-2-benzoxazolyl)piperazine(0.933 g) as a pale-yellow powder.

[1295] (4) Using the above-mentioned compound (502 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-benzoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(428 mg) was obtained as a white powder.

[1296] (5) The above-mentioned compound (424 mg) was dissolved inchloroform (10 mL), and 5 mol/L hydrochloric acid-ethyl acetate (5 mL)was added thereto. The mixture was stirred at room temperature for 18 hrand the reaction mixture was concentrated under reduced pressure. Theresidue was washed with ethanol to give the title compound (302 mg) as awhite powder.

[1297]¹H-NMR(DMSO-d₆)δ1.94-2.26(1H,m), 2.80-3.00(1H,m),3.00-4.30(15H,m), 4.45-4.78(3H,m), 7.56(1H,dd,J=8.4,1.8 Hz),7.66(1H,d,J=8.4 Hz), 7.83(1H,d,J=1.5 Hz), 9.05(1H,brs), 10.43(1H,brs).

Example 240

[1298] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1299] (1) 2-Bromo-5-nitroaniline (10 g) was dissolved inN-methyl-2-pyrrolidone (50 mL), and potassium ethylxanthate (14.8 g) wasadded thereto. The mixture was stirred at 140° C. with heating. Thereaction mixture was concentrated under reduced pressure, and water (300mL) and conc. hydrochloric acid (10 mL) were added to the residue. Theprecipitated solid was collected by filtration, which was then dissolvedin 1 mol/L aqueous sodium hydroxide solution (80 mL). After washing withchloroform, 1 mol/L hydrochloric acid was added thereto, and theprecipitated solid was collected by filtration to give2-mercapto-5-nitrobenzothiazole (8.43 g) as an orange powder.

[1300] (2) Sodium hydride (contained by 60%, 1.05 g) was suspended inDMF (50 mL) and the above-mentioned compound (8.43 g) was added theretounder ice-cooling. After the mixture was stirred for 30 min, methyliodide (2.72 mL) was added thereto under ice-cooling. The mixture wasstirred at room temperature for 2 hr. The reaction mixture was added towater, and the mixture was extracted with ethyl acetate (insolublematerial was removed by filtration). The extract was washed successivelywith water and brine and concentrated under reduced pressure to give2-methylthio-5-nitrobenzothiazole (4.82 g) as a pale-brown powder.

[1301] (3) The above-mentioned compound (3.33 g) was dissolved inethanol (70 mL), and chloride dihydrate (II) (14.0 g) was added thereto.The mixture was refluxed for 1 hr. The reaction mixture was concentratedunder reduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted withchloroform (insoluble material was filtered off). The extract was washedwith brine and concentrated under reduced pressure to give5-amino-2-methylthiobenzothiazole (2.54 g) as a red-orange solid.

[1302] (4) The above-mentioned compound (2.54 g) was suspended in water(40 mL) and conc. hydrochloric acid (3.75 mL) was added thereto underice-cooling. Thereto was added dropwise a solution of sodium nitrite(1.00 g) in water (10 mL) under ice-cooling. After stirring the reactionmixture for 20 min, 5% aqueous potassium carbonate solution (20 mL) wasadded dropwise under ice-cooling. This reaction mixture was addeddropwise under ice-cooling to a solution of copper cyanide (2.35 g) andpotassium cyanide (3.44 g) in water (40 mL) prepared separately. Afterstirring under ice-cooling for 1 hr, the mixture was stirred at 50° C.for 10 min with heating. The reaction mixture was added to water (50mL), and the mixture was extracted with ethyl acetate (insolublematerial was filtered off). The extract was washed with brine, andconcentrated under reduced pressure to give5-cyano-2-methylthiobenzothiazole (1.96 g).

[1303] (5) Using the above-mentioned compound (0.645 g) and piperazine(8.08 g), and in the same manner as in Example 189 (1),1-(5-cyano-2-benzothiazolyl)piperazine (0.601 g) was obtained as a brownsolid.

[1304] (6) Using the above-mentioned compound (601 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(649 mg) was obtained as a pale-orange powder.

[1305] (7) Using the above-mentioned compound (649 mg), and in the samemanner as in Example 239 (5), the title compound (500 mg) was obtainedas a white powder.

[1306]¹H-NMR(DMSO-d₆)δ2.04-2.28(1H,m), 2.82-3.00(1H,m),3.00-4.30(15H,m), 4.43-4.80(3H,m), 7.53(1H,dd,J=8.2,1.5 Hz),7.93(1H,d,J=1.5 Hz), 8.07(1H,d,J=8.2 Hz), 9.08(1H,brs), 10.51(1H,brs).

Example 241

[1307] Synthesis of3-{(2S,4S)-4-[4-(6-cyano-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1308] (1) Sodium hydride (containing by 60%, 6.15 g) was suspended inDMF (120 mL) and 2-mercapto-6-nitrobenzothiazole (20 g) was addedthereto under ice-cooling. After completion of bubbling, methyl iodide(26.4 mL) was added thereto. The mixture was stirred at room temperaturefor 18 hr. Water (800 mL) was added to the reaction mixture, and theprecipitated solid was collected by filtration to give2-methylthio-6-nitrobenzothiazole (21.2 g) as a pale-yellow powder.

[1309] (2) Using the above-mentioned compound (10 g) and tin(II)chloride (41.9 g), and in the same manner as in Example 240 (3),6-amino-2-methylthiobenzothiazole (7.75 g) was obtained as a whitesolid.

[1310] (3) Using the above-mentioned compound (2.59 g), sodium nitrite(1.00 g), copper cyanide (2.35 g) and potassium cyanide (3.44 g), and inthe same manner as in Example 240 (4), 6-cyano-2-mercaptobenzothiazole(2.22 g) was obtained as a brown solid.

[1311] (4) Using the above-mentioned compound (2.04 g) and piperazine(8.82 g), and in the same manner as in Example 189 (1),1-(6-cyano-2-benzothiazolyl)piperazine (2.02 mg) was obtained as abrown-reddish solid.

[1312] (5) Using the above-mentioned compound (538 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-cyano-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(526 mg) was obtained as an orange powder.

[1313] (6) Using the above-mentioned compound (526 mg), and in the samemanner as in Example 239 (5), the title compound (394 mg) was obtainedas a white powder.

[1314]¹H-NMR(DMSO-d₆)δ2.00-2.30(1H,m), 2.80-3.00(1H,m),3.00-4.30(15H,m), 4.42-4.80(3H,m), 7.59(1H,d,J=8.4 Hz),7.72(1H,dd,J=8.1,1.5 Hz), 8.39(1H,d,J=1.5 Hz), 9.06(1H,brs),10.58(1H,brs).

Example 242

[1315] Synthesis of3-{(2S,4S)-4-[4-(6-trofluoromethyl-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1316] (1) 4-Amino-3-bromobenzotrifluoride (2.40 g) was dissolved inN-methyl-2-pyrrolidone (10 mL), and potassium ethylxanthate (3.52 g) wasadded thereto. The mixture was stirred at 160° C. for 3 hr with heating.Water (300 mL) was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed successively withwater and brine, and concentrated under reduced pressure to give6-trifluoromethyl-2-mercaptobenzothiazole (607 mg) as an orange powder.

[1317] (2) Using the above-mentioned compound (607 mg), sodium hydride(containing by 60%, 155 mg) and methyl iodide (241 mL), and in the samemanner as in Example 236 (1),6-trifluoromethyl-2-methylthiobenzothiazole (665 mg) was obtained as abrown solid.

[1318] (3) Using the above-mentioned compound (0.665 g) and piperazine(11.5 g), and in the same manner as in Example 189 (1),1-(6-trifluoromethylbenzothiazolyl)piperazine (0.56 g) was obtained as awhite powder.

[1319] (4) Using the above-mentioned compound (560 mg) and the titlecompound (532 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-trifluoromethyl-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(477 mg) was obtained as a white powder.

[1320] (5) Using the above-mentioned compound (477 mg), and in the samemanner as in Example 186 (2), the title compound (403 mg) was obtainedas a white powder.

[1321]¹H-NMR(DMSO-d₆)δ2.05-2.33(1H,m), 2.79-3.00(1H,m), 3.00-3.29(2H,m),3.29-4.30(13H,m), 4.45-4.80(3H,m), 7.58-7.70(2H,m), 8.34(1H,s),9.10(1H,brs), 10.72(1H,brs).

Example 243

[1322] Synthesis of3-{(2S,4S)-4-[4-(6-methoxy-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1323] (1) Using 2-chloro-6-methoxybenzothiazole (1 g) and piperazine(8.63 g), and in the same manner as in Example 189 (1),1-(6-methoxybenzothiazolyl)piperazine (1.22 g) was obtained as apale-brown powder.

[1324] (5) Using the above-mentioned compound (549 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-methoxy-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(420 mg) was obtained as a white powder.

[1325] (6) Using the above-mentioned compound (420 mg), and in the samemanner as in Example 186 (2), the title compound (393 mg) was obtainedas a white powder.

[1326]¹H-NMR(DMSO-d₆)δ2.22-2.41(1H,m), 2.90-3.20(3H,m),3.25-4.20(13H,m), 3.77(3H,s), 4.42-4.81(3H,m), 6.96(1H,dd,J=8.9,2.6 Hz),7.47(1H,d,J=8.8 Hz), 7.50(1H,d,J=2.6 Hz).

Example 244

[1327] Synthesis of3-{(2S,4S)-4-[4-(6-isopropoxy-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1328] (1) 4-Isopropoxyaniline (24.2 g) was dissolved in acetic acid(300 mL), and a mixture of bromine (8.25 mL) and acetic acid (80 mL) wasadded dropwise. After stirring at room temperature for 2 hr, thereaction mixture was concentrated under reduced pressure. Water wasadded to residue, and the mixture was extracted with diethylether. Theextract was washed successively with aqueous sodium thiosulfate solutionand brine, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give2-bromo-4-isopropoxyaniline (10.2 g) as a black brown oil.

[1329] (2) The above-mentioned compound (10.2 g) was dissolved inN-methyl-2-pyrrolidone (50 mL), and potassium ethylxanthate (14.2 g) wasadded thereto. The mixture was stirred at 140° C. for 6 hr with heating.The reaction mixture was concentrated under reduced pressure, and 1mol/L aqueous sodium hydroxide solution (50 mL) was added to theresidue. The mixture was washed with chloroform, and conc. hydrochloricacid (30 mL) was added thereto. The mixture was extracted withchloroform. The extract was concentrated under reduced pressure to give6-isopropoxy-2-mercaptobenzothiazole (12.6 g) as a black brown oil.

[1330] (3) The above-mentioned compound (11.6 g) and 2 drops of DMF wereadded to thionyl chloride (30 mL), and the mixture was stirred at roomtemperature for 18 hr. The reaction mixture was concentrated underreduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted withchloroform. The extract was concentrated under reduced pressure and theresidue was purified by silica gel chromatography to give2-chloro-6-isopropoxybenzothiazole (9.37 g) as a black oil.

[1331] (4) Using the above-mentioned compound (9.37 g) and piperazine(35.4 g), and in the same manner as in Example 189 (1),1-(6-isopropoxy-2-benzothiazolyl)piperazine (2.8 g) was obtained as ablack powder.

[1332] (5) Using the above-mentioned compound (1.25 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-isopropoxy-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.993 g) was obtained as a pale-brown powder.

[1333] (6) Using the above-mentioned compound (933 mg), and in the samemanner as in Example 186 (2), the title compound (749 mg) was obtainedas a white powder.

[1334]¹H-NMR(DMSO-d₆)δ1.26(6H,d,J=6.0 Hz), 2.20-2.40(1H,m),2.90-3.20(3H,m), 3.28-4.12(14H,m), 4.39-4.80(3H,m), 6.92(1H,dd,J=8.8,2.6Hz), 7.44(1H,d,J=8.8 Hz), 7.48(1H,d,J=2.6 Hz), 9.18(1H,brs),10.90(1H,brs).

Example 245

[1335] Synthesis of3-{(2S,4S)-4-[4-(5-nitro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1336] (1) Using 2-methylthio-5-nitrobenzothiazole [product of Example240 (2), 1.5 g] and piperazine (11.4 g), and in the same manner as inExample 189 (1), 1-(5-nitro-2-benzothiazolyl)piperazine (1.55 g) wasobtained as a yellow powder.

[1337] (2) Using the above-mentioned compound (581 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-nitro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(507 mg) was obtained as a yellow powder.

[1338] (3) Using the above-mentioned compound (507 mg), and in the samemanner as in Example 186 (2), the title compound (243 mg) was obtainedas a yellow powder.

[1339]¹H-NMR(DMSO-d₆)δ2.00-2.22(1H,m), 2.79-3.00(1H,m),3.00-4.30(15H,m), 4.42-4.80(3H,m), 7.98(1H,dd,J=8.7,2.2 Hz),8.13(1H,d,J=8.7 Hz), 8.21(1H,d,J=2.2 Hz), 9.05(1H,brs), 10.40(1H,brs).

Example 246

[1340] Synthesis of3-{(2S,4S)-4-[4-(6-nitro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1341] (1) Conc. sulfuric acid (50 mL) was added to2-chlorobenzothiazole (10 g) under ice-cooling, and conc. nitric acid (5mL) was added dropwise under ice-cooling. The mixture was stirred underice-cooling for 1 hr, and iced water (600 mL) was added to the reactionmixture. The precipitated solid was collected by filtration, which wasthen recrystallized from acetone to give 2-chloro-6-nitrobenzothiazole(6.36 g) as a pale-yellow powder.

[1342] (2) Using the above-mentioned compound (6.36 g) and piperazine(25.8 g), and in the same manner as in Example 189 (1),1-(6-nitro-2-benzothiazolyl)piperazine (1.84 g) was obtained as a yellowpowder.

[1343] (3) Using the above-mentioned compound (581 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-nitro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(664 mg) was obtained as a yellow powder.

[1344] (4) Using the above-mentioned compound (588 mg), and in the samemanner as in Example 186 (2), the title compound (495 mg) was obtainedas a yellow powder.

[1345]¹H-NMR(DMSO-d₆)δ2.00-2.26(1H,m), 2.83-3.00(1H,m),3.01-4.30(15H,m), 4.43-4.80(3H,m), 7.60(1H,d,J=9.0 Hz),8.19(1H,dd,J=9.0,2.4 Hz), 8.89(1H,d,J=2.4 Hz), 9.16(1H,brs),10.45(1H,brs).

Example 247

[1346] Synthesis of3-{(2S,4S)-4-[4-(6-fluoro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1347] (1) Using 2-bromo-4-fluoroaniline (25 g) and potassiumethylxanthate (42.2 g), and in the same manner as in Example 244 (2),6-fluoro-2-mercaptobenzothiazole (1.01 g) was obtained as a whitepowder.

[1348] (2) Using the above-mentioned compound (1.01 g), sodium hydride(containing by 60%, 0.24 g), and methyl iodide (373 mL), and in the samemanner as in Example 236 (1), 6-fluoro-2-methylthiobenzothiazole (0.928g) was obtained as a pale-yellow solid.

[1349] (3) Using the above-mentioned compound (0.928 g) and piperazine(8.02 g), and in the same manner as in Example 189 (1),1-(6-fluoro-2-benzothiazolyl)piperazine (0.627 g) was obtained as apale-yellow oil.

[1350] (4) Using the above-mentioned compound (627 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-fluoro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(535 mg) was obtained as a white powder.

[1351] (5) Using the above-mentioned compound (535 mg), and in the samemanner as in Example 186 (2), the title compound (441 mg) was obtainedas a white powder.

[1352]¹H-NMR(DMSO-d₆)δ2.05-2.38(1H,m), 2.82-4.30(16H,m),4.42-4.80(3H,m), 7.17(1H,td,J=9.0,2.7 Hz), 7.52(1H,dd,J=9.0,4.8 Hz),7.79(1H,dd,J=8.7,2.7 Hz), 9.09(1H,brs), 10.72(1H,brs).

Example 248

[1353] Synthesis of3-{(2S,4S)-4-[4-(5-chloro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1354] (1) Using 5-chloro-2-mercaptobenzothiazole (25 g), sodium hydride(containing by 60%, 5.45 g) and methyl iodide (8.49 mL), and in the samemanner as in Example 241 (1), 5-chloro-2-methylthiobenzothiazole (26.7g) was obtained as a white powder.

[1355] (2) Using the above-mentioned compound (10.8 g) and piperazine(43.1 g), and in the same manner as in Example 189 (1),1-(6-chloro-2-benzothiazolyl)piperazine (10.9 g) was obtained as a whitepowder.

[1356] (3) Using the above-mentioned compound (558 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-chloro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(834 mg) was obtained as a white powder.

[1357] (4) Using the above-mentioned compound (834 mg), and in the samemanner as in Example 186 (2), the title compound (735 mg) was obtainedas a white powder.

[1358]¹H-NMR(DMSO-d₆)δ2.20-2.40(1H,m), 2.89-3.20(3H,m), 3.23-3.60(4H,m),3.60-4.85(12H,m), 7.18(1H,dd,J=8.4,2.1 Hz), 7.56(1H,d,J=2.1 Hz),7.88(1H,d,J=8.4 Hz), 9.15(1H,brs), 10.86(1H,brs).

Example 249

[1359] Synthesis of3-{(2S,4S)-4-[4-(6-chloro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1360] (1) Using 2,6-dichlorobenzothiazole (1 g) and piperazine (8.44g), and in the same manner as in Example 189 (1),1-(6-chloro-2-benzothiazolyl)piperazine (1.24 g) was obtained as apale-brown solid

[1361] (2) Using the above-mentioned compound (558 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-chloro-2-benzothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(740 mg) was obtained as a white powder.

[1362] (3) Using the above-mentioned compound (647 mg), and in the samemanner as in Example 186 (2), the title compound (603 mg) was obtainedas a white powder.

[1363]¹H-NMR(DMSO-d₆)δ2.22-2.42(1H,m), 2.90-3.21(3H,m),3.30-4.20(13H,m), 4.43-4.81(3H,m), 7.36(1H,dd,J=8.5,2.2 Hz),7.52(1H,d,J=8.5 Hz), 8.01(1H,d,J=2.2 Hz), 9.25(1H,brs), 11.10(1H,brs).

Example 250

[1364] Synthesis of3-{(2S,4S)-4-[4-(1-methyl-1H-indazol-3-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1365] (1) Using 1-(1-methyl-1H-indazol-3-yl)piperazine (0.714 g) andthe title compound (0.901 g) of Reference Example 12, and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-methyl-1H-indazol-3-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.37 g) was obtained as a pale-yellow solid.

[1366]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.85-2.00(1H,m),2.42-2.55(1H,m), 2.62-2.80(4H,m), 2.83-3.22(3H,m), 3.35(1H,t,J=10.1 Hz),3.40-3.52(4H,m), 3.63-4.14(6H,m), 4.39-4.81(3H,m), 7.01(1H,t,J=7.6 Hz),7.23-7.38(2H,m), 7.67(1H,d,J=8.2 Hz).

[1367] (2) The above-mentioned compound (1.36 g) was dissolved inethanol (3.5 mL), and 4.1 mol/L hydrochloric acid-ethanol (3.5 mL) wasadded thereto. The mixture was stirred at room temperature for 15 hr.The reaction mixture was concentrated under reduced pressure, and theobtained crystal was recrystallized from ethanol to give the titlecompound (0.985 g) as a white powder.

[1368]¹H-NMR(DMSO-d₆)δ2.30-2.42(1H,m), 2.95-3.17(3H,m), 3.2-4.2(16H,m),4.46-4.78(3H,m), 7.02-7.08(1H,m), 7.35-7.42(1H,m), 7.51(1H,d,J=8.6 Hz),7.81(1H,d,J=8.2 Hz), 9.17(1H,brs), 10.86(1H,brs), 12.40(1H,brs).

Example 251

[1369] Synthesis of3-{(2S,4S)-4-[4-(1-phenyl-1H-indazol-3-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1370] (1) Using 1-(1-phenyl-1H-indazol-3-yl)piperazine (0.918 g) andthe title compound (0.901 g) of Reference Example 12, and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(1-phenyl-1H-indazol-3-yl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.23 g) was obtained as a white solid.

[1371]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.47(4.5H,s), 1.88-2.04(1H,m),2.45-2.57(1H,m), 2.66-3.18(7H,m), 3.38(1H,t,J=9.9 Hz), 3.50-4.15(7H,m),4.39-4.80(3H,m), 7.11(1H,t,J=7.5 Hz), 7.24-7.32(1H,m), 7.40(1H,t,J=7.6Hz), 7.49(2H,t,J=7.5 Hz), 7.66-7.78(4H,m).

[1372] (2) The above-mentioned compound (1.22 g) was dissolved inethanol (3 mL), and 4.1 mol/L hydrochloric acid-ethanol (6 mL) was addedthereto. The mixture was stirred at room temperature for 14 hr. Theprecipitated solid was collected by filtration to give the titlecompound (0.823 g) as a white powder.

[1373]¹H-NMR(DMSO-d₆)δ2.30-2.46(1H,m), 2.96-3.18(3H,m), 3.3-4.2(13H,m),4.46-4.79(3H,m), 7.17-7.25(1H,m), 7.33(1H,t,J=7.4 Hz), 7.46-7.58(3H,m),7.74(2H,d,J=7.6 Hz), 7.81(1H,d,J=8.6 Hz), 7.98(1H,d,J=8.2 Hz),9.18(1H,brs), 10.94(1H,brs), 12.50(1H,brs).

Example 252

[1374] Synthesis of3-{(2S,4S)-4-[4-(3-benz[d]isoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1375] (1) Hydroxylammonium hydrochloride (15 g) was dissolved in 10%aqueous sodium hydroxide solution (220 mL), and a solution of ethylsalicylate (24 g) in 1,4-dioxane (70 mL) was gradually added, and themixture was stirred at room temperature for 5 hr. The reaction mixturewas concentrated until the amount thereof became almost the half, andacidified with conc. hydrochloric acid. The precipitated solid wascollected by filtration, which was then recrystallized from methanol togive salicylhydroxamic acid (12 g) as white crystals.

[1376] (2) The above-mentioned compound (12 g) was suspended intetrahydrofuran (30 mL) and thionyl chloride (13 mL) was added thereto.The mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated under reduced pressure, and the residue wasdissolved in 1,4-dioxane (30 mL). To this solution was gradually addedtriethylamine (33 mL), and the mixture was stirred at room temperaturefor 2 hr. The reaction mixture was acidified with conc. hydrochloricacid, extracted with toluene. The extract was washed successively withwater and brine, dried and concentrated under reduced pressure. Theresidue was washed with diisopropyl ether to give3-hydroxybenz[d]isoxazole (3.7 g) as a pale-brown powder.

[1377] (3) Pyridine (1.2 mL) and phosphorus oxychloride (2.1 mL) wereadded to the above-mentioned compound (2.0 g), and the mixture wasstirred at 125° C. for 5 hr. Ice was added to the reaction mixture, andthe mixture was extracted with chloroform. The extract was washed withwater, dried and concentrated under reduced pressure to give3-chlorobenz[d]isoxazole (1.7 g) as a brown solid.

[1378] (4) Using the above-mentioned compound (1.7 g) and piperazine(7.6 g), and in the same manner as in Example 189 (1),4-(3-benz[d]isoxazolyl)piperazine (0.944 g) was obtained as a graypowder.

[1379] (5) Using the title compound (0.900 g) of Reference Example 12and the above-mentioned compound (0.734 g), and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(3-benz[d]isoxazolyl)-1-piperazinyl]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.5 g) was obtained as a white solid.

[1380] (6) Using the above-mentioned compound (1.0 g), and in the samemanner as in Example 70 (2), the title compound (0.978 g) was obtainedas a white powder.

[1381]¹H-NMR(DMSO-d₆)δ2.19-2.35(1H,m), 2.90-3.16(3H,m), 3.25-3.55(4H,m),3.60-4.15(10H,m), 4.47-4.75(4H,m), 7.06-7.12(1H,m), 7.18-7.23(1H,m),7.36(1H,d,J=7.5 Hz), 7.46(1H,d,J=7.8 Hz), 9.13(1H,brs), 10.86(1H,brs)

Example 253

[1382] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-3-benz[d]isoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1383] (1) Methyl salicylate (149 g) was dissolved in acetic acid (900mL), and bromine (50 mL) was added thereto. The mixture was stirred atroom temperature for 21 hr. Water (10 L) was added to the reactionmixture, and the precipitated solid was collected by filtration, whichwas then recrystallized from methanol to give methyl 5-bromosalicylate(175 g) as white crystals.

[1384] (2) Using the above-mentioned compound (30 g), and in the samemanner as in Example 252 (1), 5-bromosalicylhydroxamic acid (24 g) wasobtained as white crystals.

[1385] (3) Using the above-mentioned compound (10 g), and in the samemanner as in Example 252 (2), 5-bromo-3-hydroxybenz[d]isoxazole (8.6 g)was obtained as a white powder.

[1386] (4) Using the above-mentioned compound (8.6 g), and in the samemanner as in Example 252 (3), 5-bromo-3-chlorobenz[d]isoxazole (7.4 g)was obtained as a white powder.

[1387] (5) Using the above-mentioned compound (7.4 g) and piperazine (21g), and in the same manner as in Example 189 (1),4-(5-bromo-3-benz[d]isoxazolyl)piperazine (6.5 g) was obtained as a graypowder.

[1388] (6) The above-mentioned compound (6.5 g) was dissolved in asolution of tetrahydrofuran (100 mL) and sodium hydroxide (1.0 g) inwater (125 mL) and benzyl chloroformate (3.9 mL) was gradually addedunder ice-cooling. The mixture was stirred at room temperature for 2 hr.The precipitated solid was collected by filtration, and washed withdiisopropyl ether to give1-benzyloxycarbonyl-4-(5-bromo-3-benz[d]isoxazolyl)piperazine (8.3 g) asa pale-brown powder.

[1389] (7) The above-mentioned compound (3.0 g) and zinc cyanide (1.1 g)was dissolved in DMF (15 mL), and tetrakistriphenylphosphinepalladium(0.633 g) was added thereto. The mixture was stirred at 85° C. for 18 hrunder a nitrogen atmosphere. The reaction mixture was added to 2 mol/Laqueous ammonia and extracted with ethyl acetate. The extract was washedsuccessively with water and brine, dried and concentrated under reducedpressure. The residue was purified by silica gel chromatography to give1-benzyloxycarbonyl-4-(5-cyano-3-benz[d]isoxazolyl)piperazine (2.1 g) asa white solid.

[1390] (8) The above-mentioned compound (1.5 g) was suspended inmethanol (60 mL), and ammonium formate (1.8 g) and 5% palladium carbon(0.230 g) were added thereto. The mixture was refluxed for 0.5 hr. Thereaction mixture was filtrated and the filtrate was concentrated underreduced pressure. Saturated aqueous sodium hydrogencarbonate solutionwas added to the residue, and the mixture was extracted with chloroform.The extract was dried and concentrated under reduced pressure to give amixture (1.1 g) containing 4-(5-cyano-3-benz[d]isoxazolyl)piperazine asa white solid.

[1391] (9) Using the title compound (904 mg) and the above-mentionedcompound (681 mg), and in the same manner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-3-benz[d]isoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(778 mg) was obtained as a white solid.

[1392] (10) Using the above-mentioned compound (778 mg), and in the samemanner as in Example 70 (2), the title compound (349 mg) was obtained asa white powder.

[1393]¹H-NMR(DMSO-d₆)δ2.15-2.40(1H,m), 2.90-3.20(3H,m),3.25-4.20(14H,m), 4.47-4.77(4H,m), 7.86(1H,d,J=8.7 Hz),8.06(1H,dd,J=8.7,1.2 Hz), 8.81(1H,brs), 9.11(1H,brs), 10.65(1H,brs).

Example 254

[1394] Synthesis of3-{(2S,4S)-4-[4-(5-methoxy-3-benz[d]isoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1395] (1) 5-Methoxysalicylic acid (41 g) was dissolved in acetonitrile(500 mL), and ethyl iodide (20 mL) and DBU (38 mL) were added thereto.The mixture was refluxed for 6 hr. The reaction mixture was concentratedunder reduced pressure, and 1 mol/L hydrochloric acid was added to theresidue. The mixture was extracted with ethyl acetate. The extract waswashed successively with saturated aqueous sodium hydrogencarbonatesolution and brine, dried and concentrated under reduced pressure togive a mixture (44 g) containing ethyl 5-methoxysalicylate as a brownoil.

[1396] (2) Using the above-mentioned compound (44 g), and in the samemanner as in Example 252 (1), 5-methoxysalicylhydroxamic acid (33 g) wasobtained as white crystals.

[1397] (3) Using the above-mentioned compound (33 g), and in the samemanner as in Example 252 (2), 3-hydroxy-5-methoxybenz[d]isoxazole (5.9g) was obtained as a pale-brown powder.

[1398] (4) Using the above-mentioned compound (5.9 g), and in the samemanner as in Example 252 (3), a mixture (4.2 g) containing3-chloro-5-hydroxybenz[d]isoxazole was obtained as a black oil.

[1399] (5) Piperazine (19 g) was melted by heating at 140° C., and theabove-mentioned title compound (4.2 g) was added thereto. After stirringat 140° C. for 1 hr, the mixture was poured into iced water andextracted with chloroform. After drying, the solvent was evaporatedunder reduced pressure, and the residue was diluted with ethyl acetateand extracted with 1 mol/L hydrochloric acid. The aqueous layer wasbasified with 2 mol/L aqueous sodium hydroxide solution and extractedwith chloroform. After drying, the solvent was evaporated under reducedpressure to give 4-(5-methoxy-3-benz[d]isoxazolyl)piperazine (804 mg) asa black solid.

[1400] (6) Using the title compound (0.900 g) of Reference Example 12and the above-mentioned compound (0.804 g), and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methoxy-3-benz[d]isoxazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.0 g) was obtained as white amorphous.

[1401] (7) Using the above-mentioned compound (1.0 g), and in the samemanner as in Example 70 (2), the title compound (0.693 g) was obtainedas a white powder.

[1402]¹H-NMR(DMSO-d₆)δ2.20-2.40(1H,m), 2.90-3.19(3H,m), 3.30-3.60(4H,m),3.65-4.15(13H,m), 4.30-4.76(4H,m), 6.65(1H,dd,J=8.7,2.4 Hz),6.97(1H,d,J=2.4 Hz), 7.35(1H,d,J=8.7 Hz), 10.15(1H,brs), 10.95(1H,brs).

Example 255

[1403] Synthesis of3-{(2S,4S)-4-[4-(3-benz[d]isothiazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine1.5 oxalate

[1404] (1) Using 1-(3-benz[d]isothiazolyl)piperazine (385 mg) and thetitle compound (500 mg) of Reference Example 12, and in the same manneras in Example 70 (1),3-{(2S,4S)-4-[4-(3-benz[d]isothiazolyl)-1-piperazinyl]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(716 mg) was obtained as a white powder.

[1405] (2) The above-mentioned compound (709 mg) was dissolved inmethanol (10 mL), and 4 mol/L hydrochloric acid-ethyl acetate (10 mL)was added thereto. The mixture was stirred at room temperature for 19hr. The precipitated solid was collected by filtration, and saturatedaqueous sodium hydrogencarbonate solution was added thereto. The mixturewas extracted with chloroform. The extract was concentrated underreduced pressure, and the residue was dissolved in ethanol (10 mL), andoxalic acid (130 mg) was added thereto. The precipitated solid wascollected by filtration to give the title compound (150 mg) as a whitepowder.

[1406]¹H-NMR(DMSO-d₆)δ1.60-1.81(1H,m), 2.78-2.85(4H,m), 2.89-3.24(4H,m),3.52-3.99(7H,m), 4.43-4.74(4H,m), 7.39-7.48(1H,m), 7.53-7.60(1H,m),8.01-8.09(2H,m).

Example 256

[1407] Synthesis of3-{(2S,4S)-4-[4-(2-oxazolo[4,5-b]pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1408] (1) 2-Amino-3-hydroxypyridine (5.51 g) was dissolved in pyridine(100 mL), and potassium ethylxanthate (8.82 g) was added thereto. Themixture was refluxed for 2 hr. Iced water (400 mL) was added to thereaction mixture, and concentrated hydrochloric acid (40 mL) was addedthereto. The mixture was extracted with chloroform and the extract waswashed with brine and concentrated under reduced pressure to give1,3-oxazolo[4,5-b]pyridine-2-thiol (5.13 g) as a pale-brown powder.

[1409] (2) The above-mentioned compound (5 g) and 2 drops of DMF wereadded to thionyl chloride (20 mL). The mixture was refluxed for 1 hr.The reaction mixture was concentrated under reduced pressure to give2-chloro-1,3-oxazolo[4,5-b]pyridine (5.08 g) as a pale-brown powder.

[1410] (3) Using the above-mentioned compound (3.09 g) and piperazine(5.17 g), and in the same manner as in Example 239 (3),1-(2-oxazolo[4,5-b]pyridyl)piperazine (1.15 g) was obtained as ayellowish brown powder.

[1411] (4) Using the above-mentioned compound (1.15 g) and the titlecompound (0.601 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-oxazolo[4,5-b]pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.635 g) was obtained as a white solid.

[1412] (5) Using the above-mentioned compound (635 mg), and in the samemanner as in Example 186 (2), the title compound (293 mg) was obtainedas a white powder.

[1413]¹H-NMR(DMSO-d₆)δ2.02-2.30(1H,m), 2.83-3.00(1H,m), 3.00-3.20(2H,m),3.20-3.48(4H,m), 3.48-4.30(9H,m), 4.40-4.80(3H,m), 7.16(1H,dd,J=7.8,5.4Hz), 7.95(1H,d,J=7.8 Hz), 8.22(1H,d,J=5.4 Hz), 9.09(1H,brs),10.59(1H,brs)

Example 257

[1414] Synthesis of3-((2S,4S)-4-{4-[2-(1-ethoxycarbonyl-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinetrihydrochloride

[1415] (1) Using ethyl2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate (2.00 g) andpiperazine (19.7 g), and by a reaction at 100° C. in the same manner asin Example 196 (1),1-[2-(1-ethoxycarbonyl-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]piperazine(2.37 g) was obtained as an oil.

[1416] (2) Using the above-mentioned compound (2.37 g) and the titlecompound (1.87 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[2-(1-ethoxycarbonyl-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(3.29 g) was obtained as a pale-yellow solid.

[1417] (3) The above-mentioned compound (1.10 g) was dissolved indichloromethane (10 mL), and trifluoroacetic acid (5 mL) was addedthereto. The mixture was stirred at room temperature for 1.5 hr. Thesolvent was evaporated under reduced pressure, and the residue wasdissolved in ethyl acetate. 4 mol/L Hydrochloric acid-ethyl acetatesolution (1 mL) was added thereto, and the precipitated solid wascollected by filtration to give the title compound (1.05 g) as a whitepowder.

[1418]¹H-NMR(500 MHz,DMSO-d₆)δ1.15(3H,t,J=7.1 Hz), 1.61(6H,s),2.16-2.36(1H,m), 2.90-4.80(19H,m), 4.10(2H,q,J=7.1 Hz),7.64(1H,d,J=10Hz), 8.10(1H,d,J=10Hz), 8.22(1H,s), 9.11(1H,brs),10.85(1H,brs).

Example 258

[1419] Synthesis of3-((2S,4S)-4-{4-[2-(1-carboxy-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinetrihydrochloride

[1420] (1)3-((2S,4S)-1-tert-Butoxycarbonyl-4-{4-[2-(1-ethoxycarbonyl-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine[product of Example 257 (2), 608 mg] was dissolved in ethanol (2 mL). Asolution of lithium hydroxide monohydrate (85 mg) in water (1 mL) wasadded, and the mixture was stirred at 60° C. for 2 hr. Dilutehydrochloric acid was added to the reaction mixture to make the pH 6.The mixture was extracted with chloroform. The extract was dried andconcentrated under reduced pressure to give3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[2-(1-carboxy-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(580 mg) as a pale-yellow powder.

[1421] (2) Using the above-mentioned compound (579 mg), and in the samemanner as in Example 257 (3), the title compound (477 mg) was obtainedas a white powder.

[1422]¹H-NMR(500 MHz,DMSO-d₆)δ1.59(6H,s), 2.11-2.31(1H,m),2.82-4.20(16H,m), 4.47-4.74(3H,m), 7.64(1H,d,J=10Hz), 8.09(1H,d,J=10Hz),8.22(1H,s), 9.07(1H,brs), 10.68(1H,brs), 12.85(1H,brs).

Example 259

[1423] Synthesis of3-{(2S,4S)-4-[4-(2-methyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1424] (1) Phosphorus oxychloride (30 mL) was added to4-hydroxy-2-methylquinoline (10 g), and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was concentrated underreduced pressure, and saturated aqueous sodium carbonate solution wasadded to the residue under ice-cooling. The mixture was extracted withethyl acetate. The extract was washed with brine, and concentrated underreduced pressure to give 4-chloro-2-methylquinoline (11.2 g) as a blackoil.

[1425] (2) Using the above-mentioned compound (5.33 g) and piperazine(25.8 g), and in the same manner as in Example 189 (1),1-(2-methyl-4-quinolyl)piperazine (4.19 g).

[1426] (3) Using the above-mentioned compound (500 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-methyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.15 g) was obtained as a pale-yellow oil.

[1427] (4) Using the above-mentioned compound (1.15 g), and in the samemanner as in Example 186 (2), the title compound (0.863 g) was obtainedas a pale-brown powder.

[1428]¹H-NMR(DMSO-d₆)δ2.20-2.42(1H,m), 2.81(3H,s), 2.91-3.20(3H,m),3.30-4.26(13H,m), 4.44-4.87(3H,m), 7.35(1H,s), 7.73(1H,t,J=7.6 Hz),8.00(1H,t,J=7.6 Hz), 8.16(1H,d,J=8.4 Hz), 8.24(1H,d,J=8.4 Hz)

Example 260

[1429] Synthesis of3-{(2S,4R)-4-[4-(2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1430] (1) Diethanolamine (20 mL) was added to4-chloro-2-trifluoromethylquinoline (5.04 g), and the mixture wasstirred at 80° C. for 19 hr. Brine was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The extract was driedand concentrated under reduced pressure. The residue was purified bysilica gel chromatography to give4-[N,N-bis(2-hydroxyethyl)amino]-2-trifluoromethylquinoline (3.40 g) asa white powder.

[1431] (2) The above-mentioned compound (1.77 g) and triethylamine (2.63mL) were dissolved in ethyl acetate (100 mL), and methanesulfonylchloride (1.28 mL) was added under ice-cooling. The mixture was stirredat room temperature for 30 min. The precipitated solid was collected byfiltration, and the filtrate was concentrated under reduced pressure togive dimesylate as an oil. This was dissolved in N-methyl-2-pyrrolidone(100 mL), and the title compound (2.02 g) of Reference Example 15 andN,N-diisopropylethylamine (3.10 mL) were added thereto. The mixture wasstirred at 100° C. for 15 hr. 10% Aqueous citric acid solution was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed successively with saturated aqueoussodium hydrogencarbonate solution and brine, dried and concentratedunder reduced pressure. The residue was purified by silica gelchromatography to give3-{(2S,4R)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.248 g) as a pale-brown powder.

[1432] (3) Using the above-mentioned compound (246 mg), and in the samemanner as in Example 133 (2), the title compound (101 mg) was obtainedas a white powder.

[1433]¹H-NMR(500 MHz,DMSO-d₆)δ2.40-2.50(1H,m), 3.00-3.18(3H,m),3.59-3.95(12H,m), 4.12-4.22(1H,m), 4.47-5.03(3H,m), 7.39(1H,s),7.75(1H,t,J=7.9 Hz), 7.88-7.91(1H,m), 8.12-8.14(2H,m), 9.30(1H,brs),10.75(1H,brs).

Example 261

[1434] Synthesis of3-{(2S,4S)-4-[4-(7-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1435] (1) Using 4-chloro-7-(trifluoromethyl)quinoline (2.5 g) andpiperazine (9.30 g), and in the same manner as in Example 189 (1),1-(7-trifluoromethyl-4-quinolyl)piperazine (3.04 g) was obtained as apale-brown solid.

[1436] (2) Using the above-mentioned compound (619 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(7-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(458 mg) was obtained as a pale-yellow oil.

[1437] (3) Using the above-mentioned compound (458 mg), and in the samemanner as in Example 186 (2), the title compound (282 mg) was obtainedas a brown powder.

[1438]¹H-NMR(DMSO-d₆)δ2.20-2.47(1H,m), 2.90-3.20(3H,m),3.30-4.30(13H,m), 4.45-4.85(3H,m), 7.46(1H,d,J=6.7 Hz),7.98(1H,dd,J=9.0,1.5 Hz), 8.43(1H,d,J=8.9 Hz), 8.62(1H,s),8.96(1H,d,J=6.7 Hz).

Example 262

[1439] Synthesis of3-{(2S,4S)-4-[4-(2-methoxycarbonyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1440] (1) Phosphorus oxychloride (100 mL) was added to kynurenic acid(25 g). The mixture was refluxed for 6 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved in1,4-dioxane (100 mL). Aqueous ammonia (400 mL) was dropwise addedthereto under ice-cooling. Water (500 mL) was added thereto, and themixture was extracted with chloroform. The extract was washed with brineand concentrated under reduced pressure to give4-chloroquinoline-2-carboxamide (27.3 g) as a black purple solid.

[1441] (2) Piperazine (12.9 g) was suspended in N-methyl-2-pyrrolidone(170 mL) and the above-mentioned compound (10.3 g) was added thereto.The mixture was stirred at 80° C. with heating. The reaction mixture wasconcentrated under reduced pressure, and the residue was added to 1mol/L hydrochloric acid (150 mL), and the mixture was washed withchloroform. The mixture was basified with aqueous sodium hydroxidesolution, and the mixture was extracted with chloroform. The extract wasconcentrated under reduced pressure to give1-(2-carbamoyl-4-quinolyl)piperazine (35.18 g) as a pale-yellow powder.

[1442] (3) Using the above-mentioned compound (2.54 g) and the titlecompound (1.26 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-carbamoyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(2.19 g).

[1443] (4) The above-mentioned compound (2.19 g) and imidazole (0.551 g)were dissolved in pyridine (20 mL), and phosphorus oxychloride (1.51 mL)was dropwise added to the reaction mixture under ice-cooling. Themixture was stirred under ice-cooling for 1 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with chloroform. The extract was concentratedunder reduced pressure and the residue was purified by silica gelchromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-cyano-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(0.658 g) as a red orange solid.

[1444] (5) 5.6 mol/L Hydrochloric acid-methanol (30 mL) was added to theabove-mentioned compound (992 mg), and the mixture was stirred at roomtemperature for 24 hr. The reaction mixture was concentrated underreduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted withchloroform and the extract was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to give a free base(670 mg) of the title compound as a pale-yellow oil. This was dissolvedin methanol (10 mL), and 5.6 mol/L hydrochloric acid-methanol (0.79 mL)was added thereto. The mixture was concentrated under reduced pressureto give the title compound (615 mg) as a pale-yellow powder.

[1445]¹H-NMR(DMSO-d₆)δ2.20-2.56(1H,m), 2.82-3.20(3H,m),3.40-4.30(13H,m), 4.00(3H,s), 4.41-4.82(3H,m), 7.63(1H,s),7.75(1H,t,J=7.8 Hz), 7.93(1H,t,J=7.8 Hz), 8.17(1H,d,J=7.8 Hz),8.24(1H,d,J=7.8 Hz), 9.20(1H,brs), 11.05(1H,brs).

Example 263

[1446] Synthesis of3-{(2S,4S)-4-[4-(2-carbamoyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1447] Using3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-carbamoyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 262 (3), 1.05 g], and in the same manner as inExample 186 (2), the title compound (696 mg) was obtained as a brownpowder.

[1448]¹H-NMR(DMSO-d₆)δ2.20-2.42(1H,m), 2.89-3.20(3H,m),3.30-4.30(13H,m), 4.44-4.83(3H,m), 7.73(1H,t,J=8.0 Hz), 7.87(1H,s),7.95(1H,t,J=8.0 Hz), 8.17(1H,d,J=8.0 Hz), 8.24(1H,brs), 8.28(1H,d,J=8.0Hz), 8.86(1H,brs), 9.18(1H,brs), 10.89(1H,brs).

Example 264

[1449] Synthesis of3-{(2S,4S)-4-[4-(3-exycarbonyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1450] (1) Diethyl ethoxymethylenemalonate (115 g) was dropwise added toaniline (50 g), and the mixture was refluxed for 1 hr. The resultingethanol was evaporated under atmospheric pressure, and the residue washeated at 200° C. and poured into diphenyl ether (750 mL). The mixturewas stirred at 220-250° C. for 2 hr with heating. The resulting ethanolwas again evaporated under atmospheric pressure, and the reactionmixture was allowed to cool to room temperature. The precipitated solidwas collected by filtration and washed with hexane to give ethyl4-hydroxyquinoline-3-carboxylate (51.0 g) as a white powder.

[1451] (2) The above-mentioned compound (51.0 g) was added to phosphorusoxychloride (121 mL), and the mixture was stirred at 60-70° C. for 2 hrwith heating. The reaction mixture was concentrated under reducedpressure, and the residue was added to iced water (1 L). The mixture wasbasified with 1 mol/L aqueous sodium hydroxide solution (500 mL) andsodium hydrogencarbonate. The mixture was extracted with ethyl acetate,washed with brine and concentrated under reduced pressure to give ethyl4-chloroquinoline-3-carboxylate (54.2 g) as a pale-brown solid.

[1452] (3) Piperazine (12.9 g) was dissolved in DMF (100 mL), and asolution of the above-mentioned compound (11.8 g) in DMF (100 mL) wasadded thereto. The mixture was stirred at room temperature for 1 hr. Thereaction mixture was added to iced water (500 mL), and the mixture wasextracted with ethyl acetate. The extract was washed successively withwater and brine, and concentrated under reduced pressure to give1-(2-ethoxycarbonyl-4-quinolyl)piperazine (7.92 g) as a pale-yellowsolid.

[1453] (4) Using the above-mentioned compound (3.42 g) and the titlecompound (2.70 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(3-ethoxycarbonyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(4.57 g) was obtained as a pale-yellow powder.

[1454] (5) The above-mentioned compound (600 mg) was dissolved inethanol (20 mL), and 4.1 mol/L hydrochloric acid-ethanol (10 mL) wasadded thereto. The mixture was stirred at room temperature for 24 hr.The reaction mixture was concentrated under reduced pressure, andsaturated aqueous sodium hydrogencarbonate solution was added to theresidue. The mixture was extracted with chloroform and the extract wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give a free base (269 mg) of the title compound.This was dissolved in ethanol (5 mL) and 4.1 mol/L hydrochloricacid-ethanol(0.42 mL) was added thereto. The mixture was concentratedunder reduced pressure to give the title compound (253 mg) as apale-yellow powder.

[1455]¹H-NMR(DMSO-d₆)δ1.41(3H,t,J=6.9 Hz), 2.22-2.46(1H,m),2.90-3.20(3H,m), 3.30-4.30(13H,m), 4.33-4.82(5H,m), 7.80(1H,t,J=7.8 Hz),8.02(1H,t,J=7.8 Hz), 8.19(1H,d,J=7.8 Hz), 8.27(1H,d,J=7.8 Hz),9.02(1H,s), 9.15(1H,brs), 10.88(1H,brs).

Example 265

[1456] Synthesis of3-{(2S,4S)-4-[4-(2-cyano-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1457]3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(2-cyano-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 262(4), 658 mg] was dissolved in chloroform (10 mL),and 4 mol/L hydrochloric acid-ethyl acetate (5 mL) was added thereto.The mixture was stirred at room temperature for 24 hr. The solvent wasevaporated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with chloroform and the extract was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givea free base (435 mg) of the title compound. This was dissolved inethanol (20 mL), and 4.1 mol/L hydrochloric acid-ethanol (0.75 mL) wasadded thereto. The mixture was concentrated under reduced pressure togive the title compound (353 mg) as a pale-yellow powder.

[1458]¹H-NMR(DMSO-d₆)δ2.20-2.45(1H,m), 2.90-3.20(3H,m),3.30-4.22(13H,m), 4.43-4.80(3H,m), 7.63(1H,s), 7.75(1H,t,J=7.8 Hz),7.89(1H,t,J=7.8 Hz), 8.01-8.19(2H,m), 9.17(1H,brs), 10.71(1H,brs).

Example 266

[1459] Synthesis of3-{(2S,4S)-4-[4-(2-phenyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1460] (1) Using 4-chloro-2-phenylquinoline (2.50 g) and piperazine(8.98 g), and in the same manner as in Example 268 (1),1-(2-phenyl-4-quinolyl)piperazine (2.72 g) was obtained.

[1461] (2) Using the above-mentioned compound (1.01 g) and the titlecompound (1.00 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-phenyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.77 g) was obtained as a white powder.

[1462] (3) The above-mentioned compound (1.75 g) was dissolved inmethanol (10 mL), and 4 mol/L hydrochloric acid-ethyl acetate (10 mL)was added thereto. The mixture was stirred at room temperature for 14hr. The precipitated solid was collected by filtration to give the titlecompound (0.970 g) as a white powder.

[1463]¹H-NMR(DMSO-d₆)δ2.20-2.45(1H,m), 2.90-3.17(3H,m),3.28-4.00(13H,m), 4.42-4.80(3H,m), 7.57(1H,s), 7.61-7.82(4H,m),7.95-8.08(1H,m), 8.16-8.31(3H,m), 8.50(1H,d,J=8.7 Hz), 9.15(1H,brs),11.06(1H,brs).

Example 267

[1464] Synthesis of3-{(2S,4S)-4-[4-(2-amino-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1465] (1) Bromine (2.32 mL) was dissolved in 5% aqueous potassiumhydroxide solution (190 mL), and a solution of4-chloroquinoline-2-carboxamide [product of Example 262 (1), 9.80 g] intetrahydrofuran (190 mL) was dropwise added thereto. The mixture wasstirred at room temperature for 30 min, and the mixture was stirred at80° C. for 1 hr with heating. The reaction mixture was filtrated and thefiltrate was added to water. The mixture was extracted with chloroform,and the extract was washed with brine and concentrated under reducedpressure. The residue was purified by silica gel chromatography to give2-amino-4-chloroquinoline (1.98 g) as a pale-yellow solid.

[1466] (2) Using the above-mentioned compound (1.98 g) and piperazine(19.1 g), and in the same manner as in Example 189 (1),1-(2-amino-4-quinolyl)piperazine (1.85 g) was obtained as a pale-brownpowder.

[1467] (3) Using the above-mentioned compound (913 mg) and the titlecompound (901 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-amino-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(465 mg) was obtained as a white solid.

[1468] (4) Using the above-mentioned compound (465 mg), and in the samemanner as in Example 186 (2), the title compound (439 mg) as obtained asa white powder.

[1469]¹H-NMR(DMSO-d₆)δ2.20-2.42(1H,m), 2.86-3.20(3H,m),3.30-4.30(13H,m), 4.41-4.84(3H,s), 6.52(1H,s), 7.46(1H,t,J=8.1 Hz),7.59-7.82(2H,m), 7.91(1H,d,J=8.1 Hz), 8.33(2H,brs), 9.14(1H,brs),10.85(1H,brs), 13.79(1H,brs)

Example 268

[1470] Synthesis of3-{(2S,4S)-4-[4-(7-chloro-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1471] (1) Piperazine (65.2 g) was melted by heating at 120° C., and4,7-dichloroquinoline (15.0 g) was added thereto. The mixture wasstirred at 120° C. for 2.5 hr and the reaction mixture was added towater. The mixture was extracted with chloroform and concentrated underreduced pressure to give 1-(7-chloro-4-quinolyl)piperazine (7.72 g).

[1472] (2) Using the above-mentioned compound (0.87 g) and the titlecompound (1.00 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(7-chloro-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.65 g) was obtained as a white powder.

[1473] (3) The above-mentioned compound (1.64 g) was suspended inmethanol (10 mL), and 4 mol/L hydrochloric acid-ethyl acetate (8.0 mL)was added thereto. The mixture was stirred at room temperature for 13hr. The precipitated solid was collected by filtration to give the titlecompound (1.04 g) as a white powder.

[1474]¹H-NMR(DMSO-d₆)δ2.10-2.37(1H,m), 2.84-4.00(16H,m),4.41-4.82(3H,m), 7.36(1H,d,J=6.9 Hz), 7.77(1H,dd,J=9.0,1.8 Hz),8.22(1H,d,J=9.0 Hz), 8.27(1H,d,J=1.8 Hz), 8.85(1H,d,J=6.9 Hz),9.18(1H,brs), 10.82(1H,brs).

Example 269

[1475] Synthesis of3-{(2S,4S)-4-[4-(2-trifluoromethyl-8-methyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1476] (1) 2-Methylaniline (5.00 g) was dissolved in 75% phosphoric acid(20 mL), and ethyl trifluoroacetoacetate (8.60 g) was dropwise addedthereto at 105° C. The mixture was stirred at 105° C. for 5.5 hr. Afterallowing to cool, the reaction mixture was added to water. Theprecipitated solid was collected by filtration to give2-trifluoromethyl-4-hydroxy-8-methylquinoline (1.84 g).

[1477] (2) The above-mentioned compound (1.82 g) was dissolved inphosphorus oxychloride (8.00 mL), and the mixture was stirred at 70° C.for 2.5 hr. The reaction mixture was concentrated under reducedpressure, and saturated aqueous sodium hydrogencarbonate solution wasadded to the residue. The mixture was extracted with chloroform and theextract was concentrated under reduced pressure to give4-chloro-2-trifluoromethyl-8-methylquinoline (1.66 g).

[1478] (3) Using the above-mentioned compound (1.65 g) and piperazine(4.00 g), and in the same manner as in Example 268 (1),1-(2-trifluoromethyl-8-methyl-4-quinolyl)piperazine (1.57 g) wasobtained.

[1479] (4) Using the above-mentioned compound (1.03 g) and the titlecompound (1.00 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-8-methyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.81 g) was obtained as a white powder.

[1480] (5) Using the above-mentioned compound (1.80 g), and in the samemanner as in Example 268 (3), the title compound (1.30 g) was obtainedas a white powder.

[1481]¹H-NMR(DMSO-d₆)δ2.20-2.45(1H,m), 2.72(3H,s), 2.90-3.20(3H,m),3.25-4.25(13H,m), 4.44-4.82(3H,m), 7.40(1H,s), 7.63(1H,dd,J=8.3,6.9 Hz),7.75(1H,d,J=6.9 Hz), 7.93(1H,d,J=8.3 Hz), 9.12(1H,brs), 10.85(1H,brs),12.65(1H,brs).

Example 270

[1482] Synthesis of3-((2S,4S)-4-{4-[2,6-bis(trifluoromethyl)-4-quinolyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[1483] (1) 4-Hydroxy-2,6-bis(trifluoromethyl)quinoline (1.28 g) wasdissolved in phosphorus oxychloride (5.0 mL), and the mixture wasstirred at room temperature for 17 hr. The reaction mixture wasconcentrated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with chloroform and concentrated under reduced pressure togive 4-chloro-2,6-bis(trifluoromethyl)quinoline (1.17 g).

[1484] (2) Using the above-mentioned compound (1.14 g) and piperazine(3.29 g), and in the same manner as in Example 189 (1),1-[2,6-bis(trifluoromethyl)-4-quinolyl]piperazine (870 mg) was obtained.

[1485] (3) Using the above-mentioned compound (0.860 g) and the titlecompound (0.86 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[2,6-bis(trifluoromethyl)-4-quinolyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(1.55 g) was obtained as a white powder.

[1486] (3) Using the above-mentioned compound (1.54 g), and in the samemanner as in Example 268 (3), the title compound (860 mg) was obtainedas a white powder.

[1487]¹H-NMR(DMSO-d₆)δ2.11-2.46(1H,m), 2.72-4.20(16H,m),4.35-4.89(3H,m), 7.54(1H,s), 8.14(1H,dd,J=9.0,1.2 Hz), 8.33(1H,d,J=9.0Hz), 8.38(1H,d,J=1.2 Hz), 9.24(1H,brs), 10.88(1H,brs).

Example 271

[1488] Synthesis of3-((2S,4S)-4-{4-[2,8-bis(trifluoromethyl)-4-quinolyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[1489] (1) Using 4-chloro-2,8-bis(trifluoromethyl)quinoline (0.500 g)and piperazine (7.19 g), and in the same manner as in Example 189 (1),1-[2,8-bis(trifluoromethyl)-4-quinolyl]piperazine (0.519 g) was obtainedas a pale-brown solid.

[1490] (2) Using the above-mentioned compound (519 mg) and the titlecompound (406 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-{4-[2,8-bis(trifluoromethyl)-4-quinolyl]-1-piperazinyl}-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(631 mg) was obtained as a white powder.

[1491] (3) Using the above-mentioned compound (547 mg), and in the samemanner as in Example 186 (2), the title compound (362 mg) was obtainedas a white powder.

[1492]¹H-NMR(DMSO-d₆)δ2.11-2.45(1H,m), 2.86-3.20(3H,m),3.30-4.30(13H,m), 4.45-4.86(3H,m), 7.52(1H,s), 7.85(1H,t,J=8.4 Hz),8.31(1H,d,J=8.4 Hz), 8.42(1H,d,J=8.4 Hz).

Example 272

[1493] Synthesis of3-{(2S,4S)-4-[4-(2-trifluoromethyl-6-methoxy-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1494] (1) 4-Methoxyaniline (5.00 g) was dissolved in 75% phosphoricacid (20 mL) and ethyl trifluoroacetoacetate (7.48 g) was dropwise addedthereto at 110° C. The mixture was stirred at 110° C. for 4 hr withheating. After allowing to cool, the reaction mixture was added tosaturated aqueous natrim hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give2-trifluoromethyl-4-hydroxy-6-methoxyquinoline (0.450 g).

[1495] (2) Using the above-mentioned compound (450 mg), and in the samemanner as in Example 270 (1),4-chloro-2-trifluoromethyl-6-methoxyquinoline (410 mg) was obtained as awhite powder.

[1496] (3) Using the above-mentioned compound (0.410 g) and piperazine(1.32 g), and in the same manner as in Example 189 (1),1-(2-trifluoromethyl-6-methoxy-4-quinolyl)piperazine (0.450 g) wasobtained.

[1497] (4) Using the above-mentioned compound (450 mg) and the titlecompound (430 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-6-methoxy-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(660 mg) was obtained as a white powder.

[1498] (5) Using the above-mentioned compound (660 mg), and in the samemanner as in Example 268 (3), the title compound (290 mg) was obtainedas a white powder.

[1499]¹H-NMR(DMSO-d₆)δ2.34-2.54(1H,m), 2.93-3.21(3H,m),3.31-4.30(13H,m), 3.97(3H,s), 4.45-4.85(3H,m), 7.31(1H,d,J=2.7 Hz),7.38(1H,s), 7.55(1H,dd,J=9.3,2.7 Hz), 8.06(1H,d,J=9.3 Hz), 9.18(1H,brs),11.84(1H,brs), 12.78(1H,brs).

Example 273

[1500] Synthesis of3-{(2S,4S)-4-[4-(2-trifluoromethyl-7-methoxy-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1501] (1) Using 3-methoxyaniline (20.0 g) and ethyltrifluoroacetoacetate (29.9 g), and in the same manner as in Example 269(1), 2-trifluoromethyl-4-hydroxy-7-methoxyquinoline (860 mg) wasobtained.

[1502] (2) Using the above-mentioned compound (850 mg), and in the samemanner as in Example 269 (2),4-chloro-2-trifluoromethyl-7-methoxyquinoline (820 mg) was obtained as awhite powder.

[1503] (3) Using the above-mentioned compound (0.820 g) and piperazine(4.00 g), and in the same manner as in Example 189 (1),1-(2-trifluoromethyl-7-methoxy-4-quinolyl)piperazine (0.840 g) wasobtained.

[1504] (4) Using the above-mentioned compound (0.830 g) and the titlecompound (0.800 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-7-methoxy-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.25 g) was obtained as a white powder.

[1505] (5) Using the above-mentioned compound (1.24 g), and in the samemanner as in Example 268 (3), the title compound (0.900 g) was obtainedas a white powder.

[1506]¹H-NMR(DMSO-d₆)δ2.28-2.48(1H,m), 2.95-3.20(3H,m),3.21-3.97(12H,m), 3.95(3H,s), 4.03-4.24(1H,m), 4.44-4.83(3H,m),7.25(1H,s), 7.36(1H,dd,J=9.9,2.6 Hz), 7.51(1H,d,J=2.6 Hz),8.04(1H,d,J=9.9 Hz), 9.16(1H,brs), 11.69(1H,brs).

Example 274

[1507] Synthesis of3-{(2S,4S)-4-[4-(2-trifluoromethyl-8-methoxy-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1508] (1) Using 2-methoxyaniline (10.0 g) and ethyltrifluoroacetoacetate (14.5 g), and in the same manner as in Example 269(1), 2-trifluoromethyl-4-hydroxy-8-methoxyquinoline (2.03 g) wasobtained.

[1509] (2) Using the above-mentioned compound (2.00 g), and in the samemanner as in Example 269 (2),4-chloro-2-trifluoromethyl-8-methoxyquinoline (1.95 g) was obtained as awhite powder.

[1510] Using the above-mentioned compound (1.95 g) and piperazine (8.00g), and in the same manner as in Example 189 (1),1-(2-trifluoromethyl-8-methoxy-4-quinolyl)piperazine (2.14 g) wasobtained.

[1511] (4) Using the above-mentioned compound (1.60 g) and the titlecompound (1.01 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-8-methoxy-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.01 g) was obtained as a white powder.

[1512] (5) Using the above-mentioned compound (1.01 g), and in the samemanner as in Example 268 (3), the title compound (0.640 g) was obtainedas a white powder.

[1513]¹H-NMR(DMSO-d₆)δ2.15-2.39(1H,m), 2.80-3.19(3H,m),3.20-4.18(13H,m), 3.99(3H,s), 4.40-4.78(3H,m), 7.29-7.33(1H,m),7.35(1H,s), 7.60-7.69(2H,m), 9.14(1H,brs), 10.71(1H,brs), 12.61(1H,brs).

Example 275

[1514] Synthesis of3-{(2S,4S)-4-[4-(8-fluoro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1515] (1) 2-Fluoroaniline (10.0 g), ethyl trifluoroacetoacetate (16.6g) and concentrated hydrochloric acid (0.1 mL) were dissolved in benzene(40 mL), and the mixture was refluxed in a reaction vessel equipped withDean-Stark trap for 7 hr. The reaction mixture was concentrated underreduced pressure and 75% phosphoric acid (40 mL) was added thereto. Themixture was stirred at 110° C. for 5 hr. The reaction mixture was addedto water, neutralized with sodium hydrogencarbonate, and extracted withethyl acetate. The extract was concentrated under reduced pressure togive 8-fluoro-4-hydroxy-2-trifluoromethylquinoline (1.77 g).

[1516] (2) Using the above-mentioned compound (1.77 g), and in the samemanner as in Example 269 (2),4-chloro-8-fluoro-2-trifluoromethylquinoline (1.70 g) was obtained as awhite powder.

[1517] (3) The above-mentioned compound (1.45 g), piperazine (0.5 g) andN,N-diisopropylethylamine (0.751 g) were dissolved in DMF (25 mL), andthe mixture was stirred at 70° C. for 6.5 hr. The reaction mixture wasadded to water, and the mixture was extracted with chloroform. Theextract was concentrated under reduced pressure and the residue waspurified by silica gel chromatography to give1-(8-fluoro-2-trifluoromethyl-4-quinolyl)piperazine (0.187 g).

[1518] (4) Using the above-mentioned compound (186 mg) and the titlecompound (187 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(8-fluoro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(302 mg) was obtained as a white powder.

[1519] (5) Using the above-mentioned compound (302 mg), and in the samemanner as in Example 186 (2), the title compound (150 mg) was obtainedas a white powder.

[1520]¹H-NMR(DMSO-d₆)δ2.23-2.48(1H,m), 2.91-3.20(3H,m),3.21-3.89(11H,m), 3.90-3.99(1H,m), 4.00-4.22(1H,m), 4.45-4.85(3H,m),7.46(1H,s), 7.65-7.78(2H,m), 7.89-8.01(1H,m), 9.16(1H,brs),11.02(1H,brs).

Example 276

[1521] Synthesis of3-{(2S,4S)-4-[4-(6-chloro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1522] (1) 4-Chloroaniline (5.00 g) was dissolved in 75% phosphoric acid(20 mL), and ethyl trifluoroacetoacetate (8.60 g) was dropwise addedthereto at 110° C. The mixture was stirred at 110° C. for 4 hr, and thenat 130° C. for 7 hr. After allowing to cool, water was added thereto.The precipitated solid was collected by filtration to give2-trifluoromethyl-4-hydroxy-6-methoxyquinoline (0.800 g).

[1523] (2) Using the above-mentioned compound (800 mg) and in the samemanner as in Example 270 (1), 4,6-dichloro-2-trifluoromethylquinoline(540 mg) was obtained as a white powder.

[1524] (3) Using the above-mentioned compound (0.54 g) and piperazine(1.50 g), and in the same manner as in Example 189 (1),1-(6-chloro-2-trifluoromethyl-4-quinolyl)piperazine (0.490 g) wasobtained.

[1525] (4) Using the above-mentioned compound (480 mg) and the titlecompound (460 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-chloro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(740 mg) was obtained as a white powder.

[1526] (5) Using the above-mentioned compound (730 mg), and in the samemanner as in Example 268 (3), the title compound (550 mg) was obtainedas a white powder.

[1527]¹H-NMR(DMSO-d₆)δ2.45-2.70(1H,m), 2.80-4.06(14H,m),4.39-4.78(5H,m), 7.42(1H,s), 7.90(1H,d,J=9.0 Hz), 8.08(1H,d,J=2.7 Hz),8.14(1H,dd,J=9.0 Hz,2.7 Hz), 9.10(1H,brs), 10.08(1H,brs).

Example 277

[1528] Synthesis of3-{(2S,4S)-4-[4-(8-chloro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1529] (1) Using 2-chloroaniline (20.0 g), and in the same manner as inExample 275 (1), 8-chloro-4-hydroxy-2-trifluoromethylquinoline (3.20 g)was obtained.

[1530] (2) Using the above-mentioned compound (3.17 g), and in the samemanner as in Example 269 (2), 4,8-dichloro-2-trifluoromethylquinoline(2.30 g) was obtained as a white powder.

[1531] (3) Using the above-mentioned compound (2.30 g), and in the samemanner as in Example 275 (3),1-(8-chloro-2-trifluoromethyl-4-quinolyl)piperazine (0.950 g) wasobtained.

[1532] (4) Using the above-mentioned compound (0.950 g) and the titlecompound (0.900 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(8-chloro-2-trifluoromethyl-4-quinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.20 g) was obtained as a white powder.

[1533] (5) Using the above-mentioned compound (1.18 g), and in the samemanner as in Example 268 (3), the title compound (0.790 g) as obtainedas a white powder.

[1534]¹H-NMR(DMSO-d₆)δ2.22-2.53(1H,m), 2.90-3.23(3H,m),3.24-3.89(11H,m), 3.90-4.01(1H,m), 4.07-4.22(1H,m), 4.44-4.85(3H,m),7.49(1H,s), 7.62-7.75(1H,m), 7.99-8.18(2H,m), 9.18(1H,brs),11.09(1H,brs).

Example 278

[1535] Synthesis of 3-{(2S,4S)-4-[4-(4-cyano-1-isoquinolyl)-1-5piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride

[1536] (1) 4-Bromo-1-hydroxyisoquinoline (1.56 g) was dissolved inN-methyl-2-pyrrolidine (25 mL), and copper cyanide (1.56 g) was addedthereto. The mixture was stirred at 180° C. for 4 hr with heating. Thereaction mixture was added to cool to 100° C. and added to an aqueoussolution (125 mL) of sodium cyanide (31.25 g). The mixture was extractedwith dichloromethane and the extract was dried and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto give 4-cyano-1-hydroxyisoquinoline (0.62 g) as a pale-yellow solid.

[1537] (2) The above-mentioned compound (916 mg) was dissolved inphosphorus oxychloride (10 mL), and the mixture was stirred at 70° C.for 5 hr with heating. Phosphorus oxychloride was evaporated underreduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted with ethylacetate, and the extract was washed with brine, dried and concentratedunder reduced pressure. The residue was purified by silica gelchromatography to give 1-chloro-4-cyanoisoquinoline (704 mg) as a whitesolid.

[1538] (3) Piperazine (4.6 g) was melted by heating at 140° C. and theabove-mentioned compound (0.500 g) was added thereto. The mixture wasstirred at 140° C. for 2 hr and water was added to the reaction mixture.The mixture was extracted with chloroform, and the extract was washedwith brine, dried and concentrated under reduced pressure to give1-(4-cyano-1-isoquinolyl)piperazine (0.491 g) as a dark brown solid.

[1539] (4) Using the above-mentioned compound (252 mg) and the titlecompound (300 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-cyano-1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(494 mg) was obtained as a pale-yellow solid.

[1540]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.87-2.02(1H,m),2.41-2.55(1H,m), 2.61-2.80(4H,m), 2.84-3.32(3H,m), 3.35(1H,dt,J=2.7,10.0Hz), 3.62-4.16(7H,m), 4.40-4.82(3H,m), 7.59(1H,t,J=8.1 Hz),7.77(1H,t,J=8.1 Hz), 8.01(1H,d,J=8.1 Hz), 8.07(1H,d,J=8.1 Hz),8.46(1H,s).

[1541] (5) The above-mentioned compound (490 mg) was dissolved intetrahydrofuran (5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (2.5mL) was added thereto. The mixture was stirred at room temperature for14 hr. The precipitated solid was collected by filtration andrecrystallized from ethanol to give the title compound (202 mg) as apale-brown powder.

[1542]¹H-NMR(DMSO-d₆)δ2.26-2.43(1H,m), 2.93-4.20(16H,m),4.44-4.78(3H,m), 7.74-7.82(1H,m), 7.75-8.05(2H,m), 8.22(1H,d,J=8.4 Hz),8.69(1H,s), 9.16(1H,brs), 10.85(1H,brs), 12.65(1H,brs).

Example 279

[1543] Synthesis of3-{(2S,4S)-4-[4-(4-chloro-1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1544] (1) Using 1-chloro-1-hydroxyisoquinoline (3.63 g), and in thesame manner as in Example 278 (2), 1,4-dichloroisoquinoline (3.95 g) wasobtained as a gray solid.

[1545] (2) Piperazine (12.6 g) was melted by heating at 140° C., and theabove-mentioned compound (2.78 g) was added thereto. The mixture wasstirred at 110° C. for 1 hr. The reaction mixture was added to water andthe mixture was extracted with chloroform. The extract was washed withbrine, dried and concentrated under reduced pressure to give1-(4-chloro-1-isoquinolyl)piperazine (3.86 g) as a dark brown solid.

[1546] (3) Using the above-mentioned compound (446 mg) and the titlecompound (450 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chloro-1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(596 mg) was obtained as a white solid.

[1547] (4) The above-mentioned compound (592 mg) was dissolved in 1.1mol/L hydrochloric acid-methanol (10 mL), and the mixture was stirred atroom temperature for 5 days. The reaction mixture was concentrated underreduced pressure, and ethanol (5 mL) was added thereto. The precipitatedsolid was collected by filtration to give the title compound (318 mg) asa pale-yellow powder.

[1548]¹H-NMR(DMSO-d₆)δ2.32-2.46(1H,m), 2.95-4.20(16H,m),4.43-4.78(3H,m), 7.74-7.82(1H,m), 7.90-7.97(1H,m), 8.14(1H,d,J=8.0 Hz),8.23(1H,d,J=8.3 Hz), 8.30(1H,s), 9.17(1H,brs), 10.83(1H,brs),12.53(1H,brs).

Example 280

[1549] Synthesis of3-{(2S,4S)-4-[4-(4-bromo-1-isoquinolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1550] (1) Using 1-bromo-1-hydroxyisoquinoline (3.11 g), and in the samemanner as in Example 278 (2), 4-bromo-1-chloroisoquinoline (3.00 g) wasobtained as a pale-brown solid

[1551] (2) Piperazine (6.94 g) was melted by heating at 140° C., and theabove-mentioned compound (2.92 g) was added thereto. The mixture wasstirred at 110° C. for 1 hr. Water was added to the reaction mixture andthe mixture was extracted with chloroform. The extract was dried andconcentrated under reduced pressure to give1-(4-bromo-1-isoquinolyl)piperazine (2.52 g) as a dark brown solid.

[1552] (3) Using the above-mentioned compound (488 mg) and the titlecompound (450 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(4-bromo-1-isoquinolyl)-1-tert-butoxycarbonyl-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(753 mg) was obtained as a pale-yellow solid.

[1553] (4) The above-mentioned compound (749 mg) was dissolved in 1.1mol/L hydrochloric acid-methanol (6 mL), and the mixture was stirred atroom temperature for 4 days. The precipitated solid was collected byfiltration to give the title compound (135 mg) as a white powder.

[1554]¹H-NMR(DMSO-d₆)δ2.32-2.46(1H,m), 2.97-3.19(3H,m),3.40-3.97(12H,m), 4.06-4.20(1H,m), 4.45-4.78(3H,m), 7.73-7.80(1H,m),7.89-7.97(1H,m), 8.08(1H,d,J=8.0 Hz), 8.22(1H,d,J=8.3 Hz), 8.40(1H,s),9.17(1H,brs), 10.94(1H,brs), 12.60(1H,brs).

Example 281

[1555] Synthesis of3-{(2S,4S)-4-[4-(4-quinazolinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1556] (1) 4-Hydroxyquinazoline (3.76 g) and 2 drops of DMF were addedto thionyl chloride (12 mL), and the mixture was refluxed for 2 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was added by small portions to piperazine (10 g) melted byheating at 140° C. Water and chloroform were added to the reactionmixture and an insoluble material was filtered off. The organic layer ofthe filtrate was separated and extracted with 1 mol/L hydrochloric acid.The aqueous layer was basified with aqueous sodium hydroxide solution,and the mixture was extracted with chloroform and concentrated underreduced pressure to give 1-(4-quinazolinyl)piperazine (1.86 g) as ayellow oil.

[1557] (2) Using the above-mentioned compound (471 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-quinazolinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(543 mg) was obtained as a yellow powder.

[1558] (3) Using the above-mentioned compound (543 mg), and in the samemanner as in Example 186 (2), the title compound (40 mg) was obtained asa white powder.

[1559]¹H-NMR(DMSO-d₆)δ2.00-2.30(1H,m), 2.80-3.00(1H,m),3.00-4.85(18H,m), 7.66-7.81(1H,m), 7.93-8.12(2H,m), 8.24(1H,d,J=8.4 Hz),8.95(1H,brs), 9.09(1H,brs), 10.84(1H,brs).

Example 282

[1560] Synthesis of3-{(2S,4S)-4-[4-(2-trifluoromethyl-4-quinazolinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[1561] (1) 2-Amino benzamide (13.6 g) was dissolved in 1,4-dioxane (50mL) and trifluoroacetic acid anhydride (16.8 mL) was dropwise addedthereto under ice-cooling. After stirring at room temperature for 1 hr,the reaction mixture was concentrated under reduced pressure. Aceticacid (50 mL) was added to the residue and the mixture was refluxed for 2hr. After allowing to cool, the precipitated solid was collected byfiltration and washed with diethyl ether to give4-hydroxy-2-trifluoromethylquinazoline (11.9 g) as a white powder.

[1562] (2) The above-mentioned compound (5 g) and 2 drops of DMF wereadded to thionyl chloride (30 mL), and the mixture was refluxed for 1hr. The reaction mixture was concentrated under reduced pressure, andthe residue was added to a solution of piperazine (6.03 g) in DMF (60mL). The mixture was stirred at room temperature for 1 hr and then at60° C. for 30 min. The reaction mixture was concentrated under reducedpressure, and water and chloroform were added thereto. An insolublematerial was filtered off. The organic layer of the filtrate wasseparated and extracted with 1 mol/L hydrochloric acid. The aqueouslayer was basified with aqueous sodium hydroxide solution, and themixture was extracted with chloroform. The extract was concentratedunder reduced pressure to give1-(2-trifluoromethyl-4-quinazolinyl)piperazine (3.75 g) as a pale-yellowsolid.

[1563] (3) Using the above-mentioned compound (1.13 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-trifluoromethyl-4-quinazolinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.51 g) was obtained as a yellow powder.

[1564] (4) Using the above-mentioned compound (1.51 g), and in the samemanner as in Example 186 (2), hydrochloride of the title compound wasobtained. Aqueous sodium hydroxide solution was added thereto, and themixture was extracted with chloroform. The extract was concentratedunder reduced pressure and the residue was purified by HPLC to give thetitle compound (450 mg) as a yellow powder.

[1565]¹H-NMR(CDCl₃)δ1.68-1.76(1H,m), 2.34-2.49(1H,m), 2.57-2.80(4H,m),.2.91-3.23(5H,m), 3.60-4.07(7H,m), 4.42-4.74(2H,m), 7.54(1H,t,J=7.8 Hz),7.80(1H,t,J=7.8 Hz), 7.91(1H,dd,J=7.8,0.8 Hz), 8.01(1H,dd,J=7.8,0.8 Hz).

Example 283

[1566] Synthesis of3-{(2S,4S)-4-[4-(2-phenyl-4-quinazolinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1567] (1) Piperazine (3.22 g) was dissolved in DMF (830 mL), and4-chloro-2-phenylquinazoline (3 g) was added thereto. The mixture wasstirred at room temperature for 6 hr. The reaction mixture wasconcentrated under reduced pressure, water and chloroform were added tothe residue and an insoluble material was filtered off. The organiclayer of the filtrate was separated and extracted with 1 mol/Lhydrochloric acid. The aqueous layer was basified with aqueous sodiumhydroxide solution, and the mixture was extracted with chloroform. Theextract was concentrated under reduced pressure to give1-(2-phenyl-4-quinazolinyl)piperazine (2.27 g) as a white solid.

[1568] (2) Using the above-mentioned compound (1.16 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-phenyl-4-quinazolinyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.66 g) was obtained as a white powder.

[1569] (3) Using the above-mentioned compound (1.66 g), and in the samemanner as in Example 186 (2), the title compound (1.21 g) was obtainedas a white powder.

[1570]¹H-NMR(DMSO-d₆)δ2.17-2.38(1H,m), 2.85-3.18(3H,m),3.30-4.90(16H,m), 7.56-7.80(4H,m), 8.04(1H,t,J=8.2 Hz), 8.22(1H,d,J=8.2Hz), 8.33(1H,d,J=8.2 Hz), 8.53(2H,d,J=8.4 Hz), 9.16(1H,brs).

Example 284

[1571] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-pyridyl)-2-oxo-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1572] (1) Using the title compound (2.10 g) of Reference Example 12 and2-aminoacetaldehyde diethyl acetal 0.984, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2,2-diethoxyethyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(3.57 g) was obtained as a pale-yellow oil.

[1573] (2) The above-mentioned compound (3.56 g) andN-benzyloxycarbonylglycine (1.54 g) were dissolved in DMF (30 mL), andHOBT (1.39 g) and EDC hydrochloride (1.61 g) were successively addedthereto. The mixture was stirred at room temperature for 2 days. Thereaction mixture was concentrated under reduced pressure, and 0.5 mol/Lhydrochloric acid was added to the residue. The mixture was extractedwith chloroform. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution and brine, dried and concentrated underreduced pressure. The residue was purified by silica gel chromatographyto give3-((2S,4S)-4-{N-[2-(1-benzyloxycarbonylamino)acetyl]-N-(2,2-diethoxyethyl)amino}-2-pyrrolidinylcarbonyl)-1-tert-butoxycarbonyl-1,3-thiazolidine(2.77 g) as a pale-brown oil.

[1574] (3) The above-mentioned compound (2.77 g) and p-toluenesulfonicacid monohydrate (0.164 g) were dissolved in toluene (100 mL), and thesolution was heated at 70° C. for 7 hr. The reaction mixture was addedto saturated aqueous sodium hydrogencarbonate solution, and the mixturewas extracted with ethyl acetate. The extract was dried and concentratedunder reduced pressure. The residue was dissolved in methanol (50 mL),and ammonium formate (1.44 g) and 10% palladium/carbon (1.93 g) wereadded thereto. The mixture was heated at 100° C. for 2 days.Furthermore, ammonium formate (1.44 g) and 10% palladium/carbon (1.93 g)were added thereto, and the mixture was stirred at 100° C. for 1 daywith heating. The reaction mixture was filtrated and the filtrate wasconcentrated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate solution was added to the residue, and the mixture wasextracted with chloroform. The extract was washed with brine, dried andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-oxo-1-piperazinyl)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(0.237 g) as a white solid.

[1575] (4) The above-mentioned compound (237 mg) andN,N-diisopropylethylamine (0.32 mL) were dissolved inN-methyl-2-pyrrolidone (5 mL), and 2-chloro-5-cyanopyridine (145 mg) wasadded thereto. The mixture was heated at 80° C. for 4 hr. The reactionmixture was added to saturated aqueous sodium hydrogencarbonatesolution, and the mixture was extracted with ethyl acetate. The extractwas washed with brine, dried and concentrated under reduced pressure.The residue was purified by silica gel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)-2-oxo-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(425 mg) as a pale-brown oil.

[1576]¹H-NMR(CDCl₃)δ1.42(4.5H,s), 1.44(4.5H,s), 1.93-2.10(1H,m),2.43-2.58(1H,m), 2.94-3.22(2H,m), 3.43-4.06(8H,m), 4.24(2H,s),4.40-4.92(3H,m), 5.20-5.38(1H,m), 6.52(1H,d,J=8.9 Hz),7.70(1H,dd,J=8.9,2.1 Hz), 8.45(1H,d,J=2.1 Hz).

[1577] (5) The above-mentioned compound (422 mg) was dissolved in ethylacetate (1 mL), and 4 mol/L hydrochloric acid-ethyl acetate (1.2 mL) wasadded thereto. The mixture was stirred at room temperature for 18 hr.The precipitated solid was collected by filtration to give the titlecompound (217 mg) as a white powder.

[1578]¹H-NMR(DMSO-d₆)δ1.86-1.96(1H,m), 2.14-2.23(1H,m), 2.60-2.75(1H,m),3.12(1H,t,J=6.2 Hz), 3.25-4.32(10H,m), 4.47(1H,t,J=10.0 Hz),4.55-4.77(2H,m), 4.95-5.10(1H,m), 7.93(1H,d,J=9.0 Hz),7.93(1H,dd,J=9.0,2.2 Hz), 8.54(1H,d,J=2.2 Hz), 8.79(1H,brs),10.29(1H,brs).

Example 285

[1579] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-pyridyl)-3-oxo-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1580] (1) N-(5-Cyano-2-pyridyl)ethylenediamine (10.0 g) andtriethylamine (9.5 mL) were dissolved in tetrahydrofuran (300 mL), andethyl 2-bromoacetate (6.9 mL) was added thereto under ice-cooling. Themixture was stirred at room temperature for 21 hr. Di-tert-butyldicarbonate (14.2 mL) was added to the reaction mixture, and the mixturewas further stirred at room temperature for 21 hr. The reaction mixturewas filtrated and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel chromatography to giveN-tert-butoxycarbonyl-N′-(5-cyano-2-pyridyl)-N-(ethoxycarbonylmethyl)ethylenediamine(17.3 g) as a white solid. compound (606 mg) of Reference Example 12,and in the same manner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-nitrophenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine387 mg) was obtained as a pale-yellow solid.

[1581] (2) Using the above-mentioned compound (387 mg), and in the samemanner as in Example 133 (2), the title compound (240 mg) was obtainedas a white powder.

[1582]¹H-NMR(500 MHz,DMSO-d₆)δ1.95-2.38(5H,m), 2.90-3.28(6H,m),3.51-4.08(7H,m), 4.48-4.75(3H,m), 7.54(2H,d,J=8.1 Hz), 8.22(2H,d,J=8.1Hz), 9.20(1H,brs), 10.60(1H,brs), 12.07(1H,brs).

Example 288

[1583] Synthesis of3-{(2S,4S)-4-[4-(2-pyrimidinyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1584] (1) 4-Cyanopyridine (50.0 g) was suspended in methanol (50 mL),and 28% sodium methoxide-methanol solution (4.14 mL) was added thereto.After stirring at room temperature for 15 min, ammonium chloride (25.7g) was added to the mixture. The mixture was stirred at room temperaturefor 24 hr. Acetone (200 mL) was added to the reaction mixture, and theprecipitated solid was collected by filtration to give 4-amidinopyridinehydrochloride (62.8 g) as a white solid.

[1585] (2) The above-mentioned compound (5.00 g) and3-dimethylamino-2-propenal (3.18 g) were suspended in methanol (30 mL),and 28% sodium methoxide-methanol solution (13.8 mL) was added thereto.The mixture was refluxed for 12 hr. The reaction mixture was filtratedand the filtrate was concentrated under reduced pressure. Water wasadded to the residue, and the mixture was extracted with chloroform. Theextract was washed with brine and dried, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography to give 4-(2-pyrimidiny)pyridine (3.45 g) as a slightlyyellow solid.

[1586] (3) The above-mentioned compound (3.14 g) was dissolved in

[1587] (2) The above-mentioned compound (17.3 g) was dissolved in1,4-dioxane (220 mL), and 1 mol/L aqueous sodium hydroxide solution (75mL) was added thereto. The mixture was stirred at room temperature for13 hr. The reaction mixture was concentrated under reduced pressure, and10% aqueous citric acid solution was added to the residue. The mixturewas extracted with ethyl acetate. The extract was washed with brine,dried, concentrated under reduced pressure and crystallized from diethylether-hexane to giveN-tert-butoxycarbonyl-N-(carboxymethyl)-N′-(5-cyano-2-pyridyl)ethylenediamine(11.7 g) as a white solid.

[1588] (3) The above-mentioned compound (3.20 g) and triethylamine (2.8mL) were dissolved in tetrahydrofuran (60 mL), and HOBT (1.84 g) and EDChydrochloride (2.30 g) were successively added. The mixture was stirredat room temperature for 6 hr. The reaction mixture was concentratedunder reduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted with ethylacetate. The extract was washed with brine, dried and concentrated underreduced pressure to give4-tert-butoxycarbonyl-1-(5-cyano-2-pyridyl)-2-oxopiperazine (2.34 g) asa white solid.

[1589] (4) The above-mentioned compound (2.34 g) was dissolved indichloromethane (50 mL), and trifluoroacetic acid (25 mL) was addedthereto under ice-cooling. The mixture was stirred for 1 hr. Thereaction mixture was concentrated under reduced pressure, and saturatedaqueous sodium hydrogencarbonate solution was added to the residue. Themixture was extracted with chloroform. The extract was washed withbrine, dried and concentrated under reduced pressure to give1-(5-cyano-2-pyridyl)-2-oxopiperazine (1.02 g) as a white solid.

[1590] (5) Using the above-mentioned compound (667 mg) and the titlecompound (901 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-pyridyl)-3-oxo-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(976 mg) was obtained as a white solid.

[1591]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.86-2.02(1H,m),2.42-2.55(1H,m), 2.78-4.83(16H,m), 7.91(1H,dd,J=8.8,2.1 Hz),8.37(1H,d,J=8.8 Hz), 8.68(1H,d,J=2.1 Hz).

[1592] (6) The above-mentioned compound (972 mg) was dissolved in ethylacetate (5 mL), and 4 mol/L hydrochloric acid-ethyl acetate (5 mL) wasadded thereto. The mixture was stirred at room temperature for 17 hr.The precipitated solid was collected by filtration to give the titlecompound (789 mg) as a white powder.

[1593]¹H-NMR(DMSO-d₆)δ1.95-2.10(1H,m), 2.80-2.94(1H,m), 3.02-3.45(5H,m),3.50-4.15(8H,m), 4.4-4.8(3H,m), 8.21(1H,d,J=8.9 Hz),8.32(1H,dd,J=8.9,2.3 Hz), 8.87-9.06(2H,m), 10.61(1H,brs).

Example 286

[1594] Synthesis of3-[(2S,4S)-4-(4-methoxycarbonylpiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[1595] (1) Using methyl isonipecotinate (0.466 g) and the title compound(0.89 g) of Reference Example 12, and in the same manner as in Example70 (1),3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-methoxycarbonylpiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(1.19 g) was obtained as a white powder.

[1596] (2) Using the above-mentioned compound (166 mg), and in the samemanner as in Example 133 (2), the title compound (132 mg) was obtainedas a white powder.

[1597]¹H-NMR(500 MHz,DMSO-d₆)δ1.88-2.13(4H,m), 2.15-2.35(1H,m),2.56-2.76(1H,m), 2.85-3.20(5H,m), 3.43-4.00(7H,m), 3.64(3H,s),4.47-4.73(3H,m), 9.20(1H,brs), 10.70(1H,brs), 11.98(1H,brs).

Example 287

[1598] Synthesis of3-{(2S,4S)-4-[4-(4-nitrophenyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1599] (1) Using 4-(4-nitrophenyl)piperidine (625 mg) and the titleacetonitrile (50 mL), and benzyl chloride (4.60 mL) was added thereto.The mixture was refluxed for 16 hr. The reaction mixture wasconcentrated to about 10 mL, and diethyl ether (10 mL) was addedthereto. The precipitated solid was collected by filtration to give1-benzyl-4-(2-pyrimidinyl)pyridine hydrochloride (5.61 g) as a whitesolid.

[1600] (4) The above-mentioned compound (5.50 g) was suspended inethanol (20 mL), and sodium borohydride (1.47 g) was added thereto underice-cooling. The mixture was stirred at room temperature for 1.5 hr andwater was added to the reaction mixture. The mixture was extracted withethyl acetate, and the extract was washed successively with water andbrine, and dried. The solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography to give1-benzyl-4-(2-pyrimidinyl)-1,2,3,6-tetrahydropyridine (4.10 g) as aslightly yellow solid.

[1601] (5) The above-mentioned compound (4.10 g) was dissolved inethanol (100 mL), and the mixture was stirred at room temperature in thepresence of 10% palladium carbon (1.10 g) under a hydrogen atomosphere(1 atm). The reaction mixture was filtrated and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give 1-benzyl-4-(2-pyrimidinyl)piperidine (3.33 g)as a colorless transparent oil.

[1602] (6) The above-mentioned compound (3.33 g) was dissolved indichloromethane (25 mL), and a solution of 1-chloroethyl chlorocarbonate(1.70 mL) in dichloromethane (5 mL) was added under ice-cooling. Themixture was refluxed for 30 min. The reaction mixture was concentratedunder reduced pressure, and the residue was dissolved in methanol (25mL). The solution was refluxed for 1 hr and 28% sodiummethoxide-methanol solution (3.40 mL) was added to the reaction mixture.After filtration, the filtrate was concentrated under reduced pressureand the residue was purified by silica gel chromatography to give4-(2-pyrimidinyl)piperidine (1.43 g) as a brown oil.

[1603] (7) Using the above-mentioned compound (1.43 g) and the titlecompound (2.39 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-pyrimidinyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(2.30 g) was obtained as a white solid.

[1604] (8) Using the above-mentioned compound (895 mg), and in the samemanner as in Example 167 (2), the title compound (227 mg) was obtainedas a slightly yellow powder.

[1605]¹H-NMR(DMSO-d₆)δ2.05-2.46(5H,m), 2.86-3.50(4H,m), 3.52-4.07(7H,m),4.42-4.79(3H,m), 7.42(1H,t,J=5.1 Hz), 8.82(2H,d,J=5.1 Hz), 9.11(1H,brs),11.01(1H,brs), 12.03(1H,brs).

Example 289

[1606] Synthesis of3-{(2S,4S)-4-[4-(5-ethyl-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1607] (1) Ethyl isonipecotinate (51.5 g) was dissolved intetrahydrofuran (400 mL) and pyridine (40 mL), and a solution of benzylchlorocarbonate (58.7 g) in tetrahydrofuran (50 mL) was dropwise addedunder ice-cooling. After stirring the mixture under ice-cooling for 1.5hr, the solvent was evaporated under reduced pressure. Water was addedto the residue, and the mixture was extracted with ethyl acetate. Theextract was washed successively with dilute hydrochloric acid, saturatedaqueous sodium hydrogencarbonate solution and brine, and dried. Thesolvent was evaporated under reduced pressure to give ethyl1-benzyloxycarbonylisonipecotinate (80.4 g) as an oil.

[1608] (2) The above-mentioned compound (42.8 g) was dissolved inisopropanol (300 mL), and hydrazine monohydrate (43 mL) was addedthereto. The mixture was refluxed for 10 hr. The solvent was evaporatedunder reduced pressure, and the residue was washed with diisopropylether and water to give 1-benzyloxycarbonylisonipecotic acid hydrazide(23.8 g) as a white solid.

[1609] (3) The above-mentioned compound (3.52 g) was dissolved intetrahydrofuran (50 mL) and pyridine (5 mL), and propionyl chloride(1.21 mL) was added thereto under ice-cooling. The mixture was stirredfor 4 hr. Water was added to the reaction mixture, and the precipitatedsolid was collected by filtration. This was suspended in1,2-dimethoxyethane (70 mL), and phosphorus oxychloride (1.40 mL) wasadded thereto. The mixture was refluxed for 4 hr. The reaction mixturewas concentrated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with chloroform, and the extract was dried and concentratedunder reduced pressure. The residue was purified by silica gelchromatography to give1-benzyloxycarbonyl-4-(5-ethyl-1,3,4-oxadiazol-2-yl)piperidine (2.29 g)as an oil.

[1610] (4) Using the above-mentioned compound (2.29 g), and in the samemanner as in Example 232 (5), 4-(5-ethyl-1,3,4-oxadiazol-2-yl)piperidinehydrobromide (1.90 g) was obtained as a white solid.

[1611] (5) Using a free base (400 mg) of the above-mentioned compoundand the title compound (553 mg) of Reference Example 12, and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-ethyl-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(856 mg) was obtained as a white powder.

[1612] (6) Using the above-mentioned compound (856 mg), and in the samemanner as in Example 257 (3), the title compound (307 mg) was obtainedas a white powder.

[1613]¹H-NMR(DMSO-d₆)δ1.25(3H,t,J=7.5 Hz), 1.90-2.44(5H,m),2.84(2H,q,J=7.5 Hz), 2.89-4.20(13H,m), 4.46-4.75(3H,m), 10.10(2H,brs),12.15(1H,brs).

Example 290

[1614] Synthesis of3-((2S,4S)-4-{4-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[1615] (1) Using 4-chlorobenzoyl chloride (1.40 μL) and1-benzyloxycarbonylisonipecotic acid hydrazide [product of Example 289(2), 3.00 g], and in the same manner as in Example 289 (3),1-benzyloxycarbonyl-4-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine(1.26 g) was obtained as a white solid.

[1616] (2) Using the above-mentioned compound (1.26 g), and in the samemanner as in Example 232 (5),4-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine hydrobromide (1.09g) was obtained as a white solid.

[1617] (3) Using a free base (556 mg) of the above-mentioned compoundand the title compound (530 mg) of Reference Example 12, and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-{4-chlorophenyl}-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(922 mg) was obtained as a white powder.

[1618] (4) Using the above-mentioned compound (896 mg), and in the samemanner as in Example 257 (3), the title compound (739 mg) was obtainedas a white powder.

[1619]¹H-NMR(500 MHz,DMSO-d₆)δ2.06-2.48(5H,m), 2.90-4.15(13H,m),4.48-4.98(3H,m), 7.69(2H,d,J=7.4 Hz), 8.01(2H,d,J=7.4 Hz), 9.14(1H,brs),10.92(1H,brs), 12.25(1H,brs).

Example 291

[1620] Synthesis of3-((2S,4S)-4-{4-[5-(3-pyridyl)-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinetrihydrochloride

[1621] (1) Using nicotinoyl chloride (1.40 g) and the product (2.08 g)of Example 289 (2), and in the same manner as in Example 289 (3),1-benzyloxycarbonyl-4-[5-(3-pyridyl)-1,3,4-oxadiazol-2-yl]piperidine(0.48 g) was obtained as a white solid.

[1622] (2) Using the above-mentioned compound (477 mg), and in the samemanner as in Example 232 (5),4-[5-(3-pyridyl)-1,3,4-oxadiazol-2-yl]piperidine hydrobromide (435 mg)was obtained as a white solid.

[1623] (3) Using a free base (256 mg) of the above-mentioned compoundand the title compound (320 mg) of Reference Example 12, and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-{3-pyridyl}-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(425 mg) was obtained as a white powder.

[1624] (4) Using the above-mentioned compound (425 mg), and in the samemanner as in Example 257 (3), the title compound (430 mg) was obtainedas a white powder.

[1625]¹H-NMR(500 MHz,DMSO-d₆)δ2.18-2.45(5H,m), 2.95-4.15(13H,m),4.48-4.77(3H,m), 7.69(1H,dd,J=8.2,5.1 Hz), 8.40-8.47(1H,m),8.82-8.85(1H,m), 9.12(1H,brs), 9.18(1H,s), 10.88(1H,brs), 12.20(1H,brs).

Example 292

[1626] Synthesis of3-((2S,4S)-4-{4-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinetrihydrochloride

[1627] (1) Using isonicotinic acid chloride (1.36 g) and the product(2.02 g) of Example 289 (2), and in the same manner as in Example 289(3),1-benzyloxycarbonyl-4-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]piperidine(0.287 g) was obtained as a white solid.

[1628] (2) Using the above-mentioned compound (287 mg), and in the samemanner as in Example 232 (5),4-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]piperidine hydrobromide (211 mg)was obtained as a white solid.

[1629] (3) Using a free base (124 mg) of the above-mentioned compoundand the title compound (157 mg) of Reference Example 12, and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-{4-pyridyl}-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(269 mg) was obtained as a white powder.

[1630] (4) Using the above-mentioned compound (268 mg), and in the samemanner as in Example 257 (3), the title compound (242 mg) was obtainedas a white powder.

[1631]¹H-NMR(500 MHz,DMSO-d₆)δ2.10-2.46(5H,m), 2.92-4.08(13H,m),4.48-4.72(3H,m), 7.97(2H,brs), 8.85-8.87(2H,m), 9.13(1H,brs),10.55(1H,brs), 11.97(1H,brs).

Example 293

[1632] Synthesis of3-{(2S,4S)-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1633] (1)3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-methoxycarbonylpiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine[product of Example 286 (1), 1.01 g] was dissolved in methanol (10 mL)and water (10 mL), and 1 mol/L sodium hydroxide (3.54 mL) was addedthereto under ice-cooling. The mixture was stirred at room temperaturefor 3 hr. Methanol was evaporated under reduced pressure and dilutehydrochloric acid was added to the residue to adjust its pH to 7. Theprecipitated solid was collected by filtration to give3-[(2S,4S)-1-tert-butoxycarbonyl-4-(4-carboxylpiperidino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(650 mg) as a white powder.

[1634] (2) The above-mentioned compound (650 mg), HOBT (290 mg) and EDChydrochloride (362 mg) were suspended in DMF (15 mL), and. hydrazinemonohydrate (114 μL) was added thereto. The mixture was stirred at roomtemperature for 18 hr. After DMF was evaporated under reduced pressure,saturated aqueous sodium hydrogencarbonate solution was added to theresidue and the mixture was extracted with chloroform. The extract wasdried and concentrated under reduced pressure. The residue was dissolvedin tetrahydrofuran (50 mL) and pyridine (5 mL), and triphosgene (190 mg)was added thereto under ice-cooling. The mixture was stirred at roomtemperature for 2 days. Water was added to the reaction mixture, and themixture was extracted with chloroform and dried. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(104 mg) as a white solid.

[1635] (3) Using the above-mentioned compound (104 mg), and in the samemanner as in Example 257 (3), the title compound (80 mg) was obtained asa white powder.

[1636]¹H-NMR(500 MHz,DMSO-d₆)δ1.82-2.32(5H,m), 2.80-4.10(13H,m),4.47-4.72(3H,m), 9.10(1H,brs), 10.41(1H,brs), 11.86(1H,brs),12.21(1H,brs).

Example 294

[1637] Synthesis of3-{(2S,4S)-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1638] (1) The product (7.46 g) of Example 289 (2) was suspended intetrahydrofuran (200 mL) and pyridine (20 mL), and tetrahydrofuransolution (20 mL) of triphosgene (3.0 g) was added thereto underice-cooling. The mixture was stirred at room temperature for 18 hr. Thesolvent was evaporated under reduced pressure, and water was added tothe residue. The mixture was extracted with ethyl acetate. The extractwas dried and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give1-benzyloxycarbonyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine(5.92 g) as an oil.

[1639] (2) The above-mentioned compound (1.02 g) was dissolved in DMF(15 mL), and potassium carbonate (0.700 g) and methyl iodide (320 μL)were added thereto. The mixture was stirred at room temperature for 15hr. The reaction mixture was concentrated under reduced pressure, andwater was added to the residue. The mixture was extracted with ethylacetate. The extract was washed with brine, dried and concentrated underreduced pressure to give1-benzyloxycarbonyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine(0.900 g) as an oil.

[1640] (3) Using the above-mentioned compound (894 mg), and in the samemanner as in Example 232 (5), 1 mol/L aqueous sodium hydroxide solutionwas added to the resulting hydrobromide. The mixture was extracted withchloroform, and concentrated under reduced pressure to give4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine (352 mg)as a pale-yellow solid.

[1641] (4) Using the above-mentioned compound (352 mg) and the titlecompound (550 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(402 mg) was obtained as a white solid.

[1642] (5) Using the above-mentioned compound (402 mg), and in the samemanner as in Example 257 (3), the title compound (375 mg) was obtainedas a white powder.

[1643]¹H-NMR(500 MHz,DMSO-d₆)δ1.90-2.32(5H,m), 2.85-4.05(13H,m),3.29(3H,s), 4.47-4.72(3H,m), 9.10(1H,brs), 10.45(1H,brs), 11.92(1H,brs).

Example 295

[1644] Synthesis of3-{(2S,4S)-4-[4-(4-methoxycarbonylmethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1645] (1) Using1-benzyloxycarbonyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine[product of Example 294 (1), 1.84 g] and methyl bromoacetate (670 μL),and in the same manner as in Example 294 (2),1-benzyloxycarbonyl-4-(4-methoxycarbonylmethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine(2.28 g) was obtained as an oil.

[1646] (2) Using the above-mentioned compound (2.26 g), and in the samemanner as in Example 232 (5), 1 mol/L aqueous sodium hydroxide solutionwas added to the resulting hydrobromide. The mixture was extracted withchloroform, and concentrated under reduced pressure to give4-(4-methoxycarbonylmethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine(1.20 g) as an oil.

[1647] (3) Using the above-mentioned compound (1.20 g) and the titlecompound (1.24 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-methoxycarbonylmethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.41 g) was obtained as a pale-yellow solid.

[1648] (4) Using the above-mentioned compound (904 mg), and in the samemanner as in Example 133 (2), the title compound (877 mg) was obtainedas a white powder.

[1649]¹H-NMR(500 MHz,DMSO-d₆)δ1.90-2.32(5H,m), 2.90-4.10(13H,m),3.57(3H,s), 4.47-4.74(3H,m), 4.64(2H,s), 9.10(1H,brs), 10.73(1H,brs),12.20(1H,brs).

Example 296

[1650] Synthesis of3-((2S,4S)-4-{4-[4-(2-morpholinoethyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinetrihydrochloride

[1651] (1) Using the product (930 mg) of Example 294 (1) and4-(2-chloroethyl)morpholine hydrochloride (685 mg), and in the samemanner as in Example 294 (2),1-benzyloxycarbonyl-4-[4-(2-morpholinoethyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidine(720 mg) was obtained as an oil.

[1652] (2) Using the above-mentioned compound (696 mg), and in the samemanner as in Example 232 (5), 1 mol/L aqueous sodium hydroxide solutionwas added to the resulting hydrobromide. The mixture was extracted withchloroform, and concentrated under reduced pressure to give4-[4-(2-morpholinoethyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidine(328 mg) as an oil.

[1653] (3) Using the above-mentioned compound (318 mg) and the titlecompound (322 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[4-(2-morpholinoethyl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(606 mg) was obtained as an oil.

[1654] (4) Using the above-mentioned compound (606 mg), and in the samemanner as in Example 258 (2), the title compound (522 mg) was obtainedas a white powder.

[1655]¹H-NMR(500 MHz,DMSO-d₆)δ1.95-2.36(5H,m), 2.90-4.15(25H,m),4.47-4.74(3H,m), 9.10(1H,brs), 10.64(1H,brs), 11.54(1H,brs),11.83(1H,brs), 12.02(1H,brs).

Example 297

[1656] Synthesis of3-((2S,4S)-4-{4-[5-oxo-4-(3-picolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinetrihydrochloride

[1657] (1) Using the product (0.932 g) of Example 294 (1) and 3-picolylchloride hydrochloride (0.605 g), and in the same manner as in Example294 (2),1-benzyloxycarbonyl-4-[5-oxo-4-(3-picolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidine(1.06 g) was obtained as an oil.

[1658] (2) Using the above-mentioned compound (1.01 g), and in the samemanner as in Example 232 (5), 1 mol/L aqueous sodium hydroxide solutionwas added to the resulting hydrobromide. The mixture was extracted withchloroform, and concentrated under reduced pressure to give4-[5-oxo-4-(3-picolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidine (0.17g) as a pale-yellow solid.

[1659] (3) Using the above-mentioned compound (170 mg) and the titlecompound (187 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[5-oxo-4-(3-picolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(236 mg) was obtained as a white powder.

[1660] (4) Using the above-mentioned compound (236 mg), and in the samemanner as in Example 257 (3), the title compound (204 mg) was obtainedas a white powder.

[1661]¹H-NMR(500 MHz,DMSO-d₆)δ1.98-2.36(5H,m), 2.93-4.05(13H,m),4.47-4.74(3H,m), 5.08(2H,s), 7.86-7.89(1H,m), 8.30-8.32(1H,m),8.79(1H,d,J=5.1 Hz), 8.85(1H,s), 9.10(1H,brs), 10.90(1H,brs),12.22(1H,brs).

Example 298

[1662] Synthesis of3-{(2S,4S)-4-[4-(2-tert-butyl-2H-tetrazol-5-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1663] (1) Isonipecotamide (19.4 g) and triethylamine (42 mL) weredissolved in dichloromethane (500 mL), and benzyloxy chlorocarbonate (24mL) was added thereto under ice-cooling. The mixture was stirred at roomtemperature for 18 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith chloroform. The extract was dried and concentrated under reducedpressure to give 1-benzyloxycarbonyl-4-carbamoylpiperidine (33.3 g) as awhite solid.

[1664] (2) The above-mentioned compound (33.3 g) and imidazole (17.3 g)were dissolved in pyridine (350 mL), and phosphorus oxychloride (47 mL)was added thereto under ice-cooling. The mixture was stirred at roomtemperature for 3 hr. The saturated aqueous sodium hydrogencarbonatesolution was added to the reaction mixture under ice-cooling, and themixture was extracted with chloroform. The extract was washed withbrine, dried, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography to give1-benzyloxycarbonyl-4-cyanopiperidine (20.6 g) as a slightly yellow oil.

[1665] (3) The above-mentioned compound (1.42 g) was dissolved inN-methyl-2-pyrrolidone (60 mL), and sodium azide (1.13 g) andtriethylamine hydrochloride (1.24 g) were added thereto. The mixture wasstirred at 150° C. for 6 hr. 1 mol/L Hydrochloric acid was added to thereaction mixture to adjust its pH to 1, and the mixture was extractedwith ethyl acetate. 10% Aqueous sodium hydroxide solution was added tothe extract, and the mixture was washed with diethyl ether. The aqueouslayer was adjusted to pH 1 with concentrated hydrochloric acid, and themixture was extracted with ethyl acetate. The extract was dried andconcentrated under reduced pressure. Trifluoroacetic acid (6 mL),tert-butanol (0.900 g) and concentrated sulfuric acid (0.16 mL) wereadded to the residue, and the mixture was stirred at room temperaturefor 3 days. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed successively with2.5 mol/L aqueous sodium hydroxide solution and brine, dried, andconcentrated under reduced pressure. The residue was purified by HPLC togive 1-benzyloxycarbonyl-4-(2-tert-butyl-2H-tetrazol-5-yl)piperidine(140 mg) as a white solid.

[1666] (4) The above-mentioned compound (140 mg) was dissolved inethanol (10 mL), and the mixture was stirred in the presence of 10%palladium/carbon (100 mg) at room temperature under a hydrogenatomosphere (1 atm) for 4 hr. The reaction mixture was filtrated and thefiltrate was concentrated under reduced pressure to give4-(2-tert-butyl-2H-tetrazol-5-yl)piperidine (85 mg) as a white solid.

[1667] (5) Using the above-mentioned compound (85 mg) and the titlecompound (117 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(2-tert-butyl-2H-tetrazol-5-yl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(192 mg) was obtained as a white powder.

[1668] (6) Using the above-mentioned compound (192 mg), and in the samemanner as in Example 257 (3), the title compound (113 mg) was obtainedas a white powder.

[1669]¹H-NMR(500 MHz,DMSO-d₆)δ1.67(9H,s), 1.95-2.30(5H,m),2.92-4.10(13H,m), 4.40-4.73(3H,m).

Example 299

[1670] Synthesis of3-((2S,4S)-4-{4-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[1671] (1) Isonipecotic acid (19.0 g) was dissolved in water (150 mL)and 1,4-dioxane (300 mL), 1 mol/L aqueous sodium hydroxide solution (150mL) and di-tert-butyl dicarbonate (35.3 g) were added thereto underice-cooling. The mixture was stirred at room temperature for 3 days.1,4-Dioxane was evaporated under reduced pressure, and 5% potassiumhydrogen sulfate was added to the residue. The precipitated solid wascollected by filtration to give 1-tert-butoxycarbonylisonipecotic acid(33.0 g) as a white solid.

[1672] (2) The above-mentioned compound (2.63 g), HOBT (2.11 g) and EDChydrochloride (2.64 g) were dissolved in DMF (50 mL), and p-anisidine(1.41 g) was added thereto. The mixture was stirred at room temperaturefor 3 hr. Water was added to the reaction mixture, and the precipitatedsolid was collected by filtration to give1-tert-butoxycarbonylisonipecotic acid 4-methoxyphenylamide (2.84 g) asa white solid.

[1673] (3) The above-mentioned compound (1.06 g) was dissolved intetrahydrofuran (30 mL), and trimethylsilylazide (845 μL),triphenylphosphine (1.66 g) and 40% diisopropyl azodicarboxylate/toluenesolution (3.20 g) was added thereto. The mixture was stirred at roomtemperature for 23 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withbrine, dried, and concentrated under reduced pressure. The residue waspurified by HPLC to give1-tert-butoxycarbonyl-4-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]piperidine(0.514 g) as a white solid.

[1674] (4) The above-mentioned compound (514 mg) was dissolved indichloromethane (10 mL), and trifluoroacetic acid (3 mL) was addedthereto at room temperature. The mixture was stirred for hr. The solventwas evaporated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with chloroform. The extract was dried and concentrated underreduced pressure to give4-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]piperidine (260 mg) as an oil.

[1675] (5) Using the above-mentioned compound (260 mg) and the titlecompound (295 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[1-(4-methoxyphenyl)-1H-tetrazol-5-yl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(427 mg) was obtained as a white powder.

[1676] (6) Using the above-mentioned compound (424 mg), and in the samemanner as in Example 133 (2), the title compound (301 mg) was obtainedas a white powder.

[1677]¹H-NMR(500 MHz,DMSO-d₆)δ1.95-2.35(5H,m), 2.87-3.95(13H,m),3.87(3H,s), 4.46-4.73(3H,m), 7.19(2H,d,J=8.8 Hz), 7.61(2H,d,J=8.8 Hz),9.10(1H,brs), 10.70(1H,brs), 12.02(1H,brs).

Example 300

[1678] Synthesis of3-{(2S,4S)-4-[4-(5-chloro-3-benzofuranyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1679] (1) Using 4-(5-chloro-3-benzofuranyl)piperidine (380 mg) and thetitle compound (404 mg) of Reference Example 12, and in the same manneras in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-chloro-3-benzofuranyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(697 mg) was obtained as a pale-yellow powder.

[1680] (2) Using the above-mentioned compound (697 mg), and in the samemanner as in Example 133 (2), the title compound (182 mg) was obtainedas a brown powder.

[1681]¹H-NMR(500 MHz,DMSO-d₆)δ2.00-2.40(5H,m), 2.90-4.14(13H,m),4.49-4.74(3H,m), 7.35(1H,dd,J=8.7,1.8 Hz), 7.61(1H,d,J=8.7 Hz),7.94(1H,s), 7.99(1H,s), 9.22(1H,brs), 10.71(1H,brs), 12.11(1H,brs).

Example 301

[1682] Synthesis of3-{(2S,4S)-4-[4-(2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1683] (1) Acetyl chloride (180 mL) was dropwise added to a mixture ofethanol (160 mL) and chloroform (180 mL) under ice-cooling. After themixture was stirred for 30 min, a solution of1-benzyloxycarbonyl-4-cyanopiperidine [product of Example 298 (2), 20.6g] in chloroform (180 mL) was added thereto under ice-cooling. Themixture was stirred at room temperature for 18 hr. The reaction mixturewas concentrated under reduced pressure to give1-benzyloxycarbonyl-4-(ethoxycarbonimidoyl)piperidine hydrochloride(28.7 g) as a white solid.

[1684] (2) The above-mentioned compound (2.88 g) and1,2-phenylenediamine (1.19 g) were dissolved in ethanol (50 mL), and themixture was refluxed for 4 hr. The reaction mixture was concentratedunder reduced pressure, and 0.5 mol/L aqueous sodium hydroxide solutionwas added to the residue. The mixture was extracted with chloroform. Theextract was washed successively with 0.2 mol/L hydrochloric acid,saturated aqueous sodium hydrogencarbonate solution and brine, anddried. The solvent was evaporated under reduced pressure and the residuewas purified by silica gel chromatography to give1-benzyloxycarbonyl-4-(2-benzimidazolyl)piperidine (2.61 g) as apale-brown solid.

[1685] (3) The above-mentioned compound (2.50 g) was dissolved inmethanol (50 mL), and the mixture was stirred in the presence of 10%palladium/carbon (500 mg) at room temperature under a hydrogenatomosphere (1 atm). The reaction mixture was filtrated and the filtratewas concentrated under reduced pressure to give4-(2-benzimidazolyl)piperidine (1.50 g) as a pale-brown solid.

[1686] (4) Using the above-mentioned compound (332 mg) and the titlecompound (450 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(2-benzimidazolyl)piperidino]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(434 mg) was obtained as a yellow solid.

[1687]¹H-NMR(CDCl₃)δ1.36(4.5H,s), 1.40(4.5H,s), 1.75-2.32(7H,m),2.43-2.56(1H,m), 2.75-4.15(10H,m), 4.38-4.82(3H,m), 7.17-7.25(2H,m),7.41(1H,brs), 7.68(1H,brs), 10.74(1H,brs).

[1688] (5) The above-mentioned compound (430 mg) was dissolved inethanol (4 mL), and 4.1 mol/L hydrochloric acid-ethanol (2.2 mL) wasadded thereto. The mixture was stirred at room temperature for 13 hr.The precipitated solid was collected by filtration to give the titlecompound (318 mg) as a white powder.

[1689]¹H-NMR(DMSO-d₆)δ2.20-2.57(5H,m), 2.95-4.07(13H,m),4.47-4.79(3H,m), 7.48-7.57(2H,m), 7.74-7.83(2H,m), 9.14(1H,brs),10.91(1H,brs), 12.18(1H,brs).

Example 302

[1690] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1691] (1) Using 1-benzyloxycarbonyl-4-(ethoxycarbonimidoyl)piperidinehydrochloride [product of Example 301 (1), 2.87 g] and3,4-diaminobenzonitrile [product of Example 231 (1), 1.46 g], and in thesame manner as in Example 301 (2),1-benzyloxycarbonyl-4-(5-cyano-2-benzimidazolyl)piperidine (2.11 g) wasobtained as a pale-brown solid.

[1692] (2) Using the above-mentioned compound (2.11 g), and in the samemanner as in Example 301 (3), 4-(5-cyano-2-benzimidazolyl)piperidine(1.44 g) was obtained as a yellow powder.

[1693] (3) Using the above-mentioned compound (498 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(463 mg) was obtained as a white solid.

[1694] (4) 4 mol/L Hydrochloric acid-1,4-dioxane (2.5 mL) was added tothe above-mentioned compound (459 mg), and the mixture was stirred atroom temperature for 10 days. The precipitated solid was collected byfiltration to give the title compound (412 mg) as a white powder.

[1695]¹H-NMR(DMSO-d₆)δ2.17-2.60(5H,m), 2.95-4.10(13H,m),4.45-4.79(3H,m), 5.7(1H,brs), 7.73(1H,d,J=8.4 Hz), 7.82(1H,d,J=8.4 Hz),8.21(1H,s), 9.13(1H,brs), 10.97(1H,brs), 12.14(1H,brs).

Example 303

[1696] Synthesis of3-{(2S,4S)-4-[4-(5-fluoro-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1697] (2) Using the product (2.87 g) of Example 301 (1) and4-fluoro-1,2-phenylenediamine [product of Example 233 (1), 1.38 g], andin the same manner as in Example 301 (2),1-benzyloxycarbonyl-4-(5-fluoro-2-benzimidazolyl)piperidine (2.72 g) wasobtained as a yellow solid.

[1698] (2) Using the above-mentioned compound (2.71 g), and in the samemanner as in Example 301 (3), 4-(5-fluoro-2-benzimidazolyl)piperidine(1.84 g) was obtained as a brown-dark solid.

[1699] (3) Using the above-mentioned compound (488 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-fluoro-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (505 mg) wasobtained as a pale-brown solid.

[1700] (4) The above-mentioned compound (501 mg) was dissolved inethanol (5.5 mL), and 4.1 mol/L hydrochloric acid-ethanol (3.7 mL) wasadded thereto. The mixture was stirred at room temperature for 3 days.The precipitated solid was collected by filtration to give the titlecompound (391 mg) as a white powder.

[1701]¹H-NMR(DMSO-d₆)δ2.17-2.55(5H,m), 2.93-4.10(13H,m),4.45-4.78(3H,m), 7.30-7.41(1H,m), 7.60(1H,dd,J=8.6,2.1 Hz),7.79(1H,dd,J=8.9,4.5 Hz), 9.14(1H,brs), 10.96(1H,brs), 12.16(1H,brs).

Example 304

[1702] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-1-methyl-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine3 hydrochloride

[1703] (1) Using the product (1.29 g) of Example 301 (1) and3-amino-4-methylaminobenzonitrile (0.61 g), and in the same manner as inExample 301 (2),1-benzyloxycarbonyl-4-(5-cyano-1-methyl-2-benzimidazolyl)piperidine(1.03 g) was obtained as a pale-brown solid

[1704] (2) Using the above-mentioned compound (1.03 g), and in the samemanner as in Example 301 (3),4-(5-cyano-1-methyl-2-benzimidazolyl)piperidine (0.549 g) was obtainedas a yellow solid.

[1705] (3) Using the above-mentioned compound (396 mg) and the titlecompound (450 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-1-methyl-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(316 mg) was obtained as a white solid.

[1706] (4) The above-mentioned compound (313 mg) was dissolved in ethylacetate (1 mL), and 4 mol/L hydrochloric acid-ethyl acetate (3 mL) wasadded thereto. The mixture was stirred at room temperature for 18 hr.The precipitated solid was collected by filtration to give the titlecompound (298 mg) as a white powder.

[1707]¹H-NMR(DMSO-d₆)δ2.13-2.43(5H,m), 2.97-3.35(5H,m),3.42-4.07(13H,m), 4.47-4.90(3H,m), 7.71(1H,d,J=8.4 Hz), 7.84(1H,d,J=8.4Hz), 8.19(1H,s), 9.14(1H,brs), 10.91(1H,brs), 12.14(1H,brs).

Example 305

[1708] Synthesis of3-{(2S,4S)-4-[4-(5-fluoro-1-methyl-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1709] (1) Using the product (2.87 g) of Example 301 (1) and4-fluoro-N1-methyl-1,2-phenylenediamine [product of Example 238 (1),1.30 g], and in the same manner as in Example 301 (2),1-benzyloxycarbonyl-4-(5-fluoro-1-methyl-2-benzimidazolyl)piperidine(2.83 g) was obtained as a brown-dark oil.

[1710] (2) Using the above-mentioned compound (2.83 g), and in the samemanner as in Example 301 (3),4-(5-fluoro-1-methyl-2-benzimidazolyl)piperidine (1.65 g) was obtainedas a brown solid.

[1711] (3) Using the above-mentioned compound (513 mg) and the titlecompound (601 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-fluoro-1-methyl-2-benzimidazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(377 mg) was obtained as a pale-brown solid.

[1712] (4) The above-mentioned compound (373 mg) was dissolved in ethylacetate (1 mL), and 4 mol/L hydrochloric acid-ethyl acetate (3.8 mL) wasadded thereto. The mixture was stirred at room temperature for 12 hr.The precipitated solid was collected by filtration to give the titlecompound (226 mg) as a white powder.

[1713]¹H-NMR(DMSO-d₆)δ2.18-2.43(5H,m), 2.97-3.37(5H,m),3.60-4.09(13H,m), 4.47-4.80(4H,m), 7.39(1H,t,J=8.7 Hz),7.57(1H,dd,J=8.7,2.0 Hz), 7.83-7.92(1H,m), 9.14(1H,brs), 10.95(1H,brs),12.14(1H,brs).

Example 306

[1714] Synthesis of3-{(2S,4S)-4-[4-(5-methyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[1715] (1) Using the product (2.50 g) of Example 301 (1) and2-amino-4-methylphenol (1.60 g), and in the same manner as in Example301 (2), 1-benzyloxycarbonyl-4-(5-methyl-2-benzoxazolyl)piperidine (2.01g) was obtained as a dark brown oil.

[1716] (2) Using the above-mentioned compound (2.00 g), and in the samemanner as in Example 301 (3), 4-(5-methyl-2-benzoxazolyl)piperidine(1.21 g) was obtained as a green solid.

[1717] (3) Using the above-mentioned compound (0.714 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.47 g) was obtained as a pale-green solid.

[1718] (4) The above-mentioned compound (1.47 g) was dissolved in 4.1mol/L hydrochloric acid-ethanol (7 mL), and the mixture was stirred atroom temperature for 6 hr. The reaction mixture was concentrated underreduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted withchloroform. The extract was dried and concentrated under reducedpressure. The residue was purified by silica gel chromatography andrecrystallized from diethyl ether to give the title compound (0.601 g)as a white powder.

[1719]¹H-NMR(DMSO-d₆)δ1.52-1.65(1H,m), 1.72-1.88(2H,m), 1.98-2.18(4H,m),2.22-2.33(1H,m), 2.40(3H,s), 2.64-3.03(7H,m), 3.07(1H,t,J=6.2 Hz),3.58-3.93(3H,m), 4.38-4.68(2H,m), 7.15(1H,dd,J=8.3,1.3 Hz),7.48(1H,d,J=1.3 Hz), 7.53(1H,d,J=8.3 Hz).

Example 307

[1720] Synthesis of3-{(2S,4S)-4-[4-(5-trifluoromethyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[1721] (1) Using the product (2.96 g) of Example 301 (1) and2-amino-4-trifluoromethylphenol (2.30 g), and in the same manner as inExample 301 (2),1-benzyloxycarbonyl-4-(5-trifluoromethyl-2-benzoxazolyl)piperidine (2.68g) was obtained as a brown oil.

[1722] (2) Using the above-mentioned compound (2.68 g), and in the samemanner as in Example 301 (3),4-(5-trifluoromethyl-2-benzoxazolyl)piperidine (1.74 g) was obtained asa pale-green oil.

[1723] (3) Using the above-mentioned compound (0.892 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-trifluoromethyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.56 g) was obtained as a white solid.

[1724] (4) The above-mentioned compound (1.47 g) was dissolved in 4.1mol/L hydrochloric acid-ethanol (7 mL), and the mixture was stirred atroom temperature for 16 hr. The reaction mixture was concentrated underreduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted withchloroform. The extract was dried and concentrated under reducedpressure. The residue was purified by silica gel chromatography andcrystallized from diethyl ether to give the title compound (0.034 g) asa white powder.

[1725]¹H-NMR(DMSO-d₆)δ1.54-1.65(1H,m), 1.74-1.89(2H,m), 2.03-2.24(4H,m),2.27-2.38(1H,m), 2.71-3.14(8H,m), 3.58-4.03(3H,m), 4.41-4.72(2H,m),7.74(1H,d,J=8.5 Hz), 7.92(1H,d,J=8.5 Hz), 8.14(1H,s).

Example 308

[1726] Synthesis of3-{(2S,4S)-4-[4-(5-methoxycarbonyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[1727] (1) Using the product (5.92 g) of Example 301 (1) and methyl3-amino-4-hydroxybenzoate (4.34 g), and in the same manner as in Example301 (2),1-benzyloxycarbonyl-4-(5-methoxycarbonyl-2-benzoxazolyl)piperidine (5.44g) was obtained as a slightly red solid.

[1728] (2) Using the above-mentioned compound (2.02 g), and in the samemanner as in Example 301 (3),4-(5-methoxycarbonyl-2-benzoxazolyl)piperidine (1.40 g) was obtained asa pale-yellow solid.

[1729] (3) Using the above-mentioned compound (0.858 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methoxycarbonyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.48 g) was obtained as a white solid.

[1730] (4) The above-mentioned compound (1.47 g) was dissolved inmethanol (2 mL), and 5.6 mol/L hydrochloric acid-methanol (2.5 mL) wasadded thereto. The mixture was stirred at room temperature for 14 hr.The reaction mixture was concentrated under reduced pressure, andsaturated aqueous sodium hydrogencarbonate solution was added to theresidue. The mixture was extracted with chloroform. The extract wasdried and concentrated under reduced pressure. The residue was purifiedby HPLC and crystallized from diethyl ether to give the title compound(0.080 g) as a white powder.

[1731]¹H-NMR(DMSO-d₆)δ1.56-1.67(1H,m), 1.74-1.89(2H,m), 2.03-2.24(4H,m),2.32-2.43(1H,m), 2.72-3.12(8H,m), 3.48-3.73(1H,m), 3.48-3.73(1H,m),3.80-3.90(1H,m), 3.88(3H,s), 3.96-4.08(1H,m), 4.42-4.72(2H,m),5.3(1H,brs), 7.82(1H,d,J=8.5 Hz), 8.00(1H,dd,J=8.5,1.7 Hz),8.24(1H,d,J=1.7 Hz).

Example 309

[1732] Synthesis of3-{(2S,4S)-4-[4-(5-ethoxycarbonyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[1733] (1) Using the product (25.0 g) of Example 301 (1) and ethyl3-amino-4-hydroxybenzoate (18.8 g), and in the same manner as in Example301 (2),1-benzyloxycarbonyl-4-(5-ethoxycarbonyl-2-benzoxazolyl)piperidine (20.0g) was obtained as a white solid.

[1734] (2) Using the above-mentioned compound (10.2 g), and in the samemanner as in Example 301 (3),4-(5-ethoxycarbonyl-2-benzoxazolyl)piperidine (7.05 g) was obtained as awhite solid.

[1735] (3) Using the above-mentioned compound (4.04 g) and the titlecompound (4.03 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(7.56 g) was obtained as a white powder.

[1736] (4) The above-mentioned compound (2.24 g) was dissolved indichloromethane (4 mL) and trifluoroacetic acid (2 mL), and the mixturewas stirred at room temperature for 15 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with chloroform. The extract was dried and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography and recrystallized from diethyl ether togive the title compound (1.18 g) as a white powder.

[1737]¹H-NMR(CDCl₃)δ1.41(3H,t,J=7.2 Hz), 1.65-2.45(8H,m),2.94-3.16(9H,m), 3.63-3.98(3H,m), 4.40(2H,q,J=7.2 Hz), 4.44-4.68(2H,m),7.51(1H,d,J=8.7 Hz), 8.07(1H,dd,J=8.7,1.8 Hz), 8.39(1H,d,J=1.8 Hz).

Example 310

[1738] Synthesis of3-{(2S,4S)-4-[4-(5-carboxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1739] (1)3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 309 (3), 4.51 g] was dissolved in ethanol (16 mL)and water (8 mL), and lithium hydroxide monohydrate (678 mg) was added.The mixture was stirred at room temperature for 3.5 hr. The reactionmixture was diluted with water, and 1 mol/L hydrochloric acid was addedto adjust its pH to 7. The mixture was extracted with chloroform. Theextract was dried and concentrated under reduced pressure to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carboxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(3.45 g) as a white powder.

[1740] (2) Using the above-mentioned compound (786 mg), and in the samemanner as in Example 167 (2), the title compound (689 mg) was obtainedas a white powder.

[1741]¹H-NMR(DMSO-d₆)δ2.10-2.45(5H,m), 2.88-4.12(13H,m),4.45-4.81(3H,m), 7.82(1H,d,J=8.7 Hz), 8.02(1H,dd,J=8.7,1.5 Hz),8.24(1H,d,J=1.5 Hz), 9.20(1H,brs), 10.45(1H,brs), 11.90(1H,brs),13.15(1H,brs).

Example 311

[1742] Synthesis of3-{(2S,4S)-4-[4-(5-carbamoyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[1743] (1)3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-carboxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 310 (1), 1.06 g] was dissolved in tetrahydrofuran (5mL), and triethylamine (0.279 mL) and isobutyl chlorocarbonate (0.263mL) were added thereto under ice-cooling. The mixture was stirred atroom temperature for 30 min. A solution of 7 mol/L ammonia-methanol (1mL) was added to the reaction mixture, and the mixture was stirred atroom temperature for 15 hr. Water was added to the reaction mixture, andthe mixture was extracted with chloroform. The extract was dried andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carbamoyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(345 mg) as a white powder.

[1744] (2) The above-mentioned compound (335 mg) was dissolved indichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), and themixture was stirred at room temperature for 7.5 hr. Saturated aqueoussodium hydrogencarbonate solution was added to the reaction mixture, andthe mixture was extracted with chloroform. The extract was dried, andconcentrated under reduced pressure to give the title compound (75 mg)as a white powder.

[1745]¹H-NMR(CDCl₃)δ1.65-1.78(1H,m), 1.95-2.47(8H,m), 2.85-3.19(8H,m),3.62-3.75(1H,m), 3.77-3.98(2H,m), 4.47-4.67(2H,m), 5.88(1H,brs),6.18(1H,brs), 7.54(1H,d,J=9.6 Hz), 7.87(1H,dd,J=9.6,1.5 Hz),8.11(1H,d,J=1.5 Hz).

Example 312

[1746] Synthesis of3-((2S,4S)-4-{4-[5-(N-methylcarbamoyl)-2-benzoxazolyl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine

[1747] (1) Using the product (1.06 g) of Example 310 (1) and 30%methylamine-ethanol solution (1 mL), and in the same manner as inExample 311 (1),3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[5-(N-methylcarbamoyl)-2-benzoxazolyl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(0.725 g) was obtained as a white powder.

[1748] (2) Using the above-mentioned compound (669 mg), and in the samemanner as in Example 311 (2), the title compound (386 mg) was obtainedas a white powder.

[1749]¹H-NMR(CDCl₃)δ1.62-1.78(1H,m), 1.92-2.38(8H,m), 2.87-3.20(11H,m),3.63-3.74(1H,m), 3.75-3.97(2H,m), 4.47-4.67(2H,m), 6.35(1H,brs),7.51(1H,d,J=8.5 Hz), 7.81(1H,dd,J=8.5,1.7 Hz), 8.04(1H,d,J=1.7 Hz).

Example 313

[1750] Synthesis of3-((2S,4S)-4-{4-[5-(N,N-dimethylcarbamoyl)-2-benzoxazolyl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidinedihydrochloride

[1751] (1) The product (1.36 g) of Example 310 (1) and dimethylaminehydrochloride (0.244 g) were dissolved in DMF, and triethylamine (0.42mL), HOBT (0.457 g) and EDC hydrochloride (0.572 g) were added thereto.The mixture was stirred at room temperature for 1.5 hr. The saturatedaqueous sodium hydrogencarbonate solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas dried and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[5-(N,N-dimethylcarbamoyl)-2-benzoxazolyl]piperidino}-2-pyrrolidinylcarbonyl)-1,3-thiazolidine(0.786 g) as a white powder.

[1752] (2) Using the above-mentioned compound (760 mg), and in the samemanner as in Example 167 (2), the title compound (634 mg) was obtainedas a white powder.

[1753]¹H-NMR(DMSO-d₆)δ2.13-2.46(5H,m), 2.84-4.10(19H,m),4.41-4.79(3H,m), 7.43(1H,dd,J=1.5,8.4 Hz), 7.75-7.78(2H,m),9.18(1H,brs), 10.63(1H,brs), 12.05(1H,brs).

Example 314

[1754] Synthesis of3-{(2S,4S)-4-[4-(5-cyano-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[1755] (1) Using the product (2.88 g) of Example 301 (1) and3-amino-4-cyanophenol (1.47 g), and in the same manner as in Example 301(2), 1-benzyloxycarbonyl-4-(5-cyano-2-benzoxazolyl)piperidine (2.43 g)was obtained as a pale-brown powder.

[1756] (2) Using the above-mentioned compound (2.43 g), and in the samemanner as in Example 301 (3), 4-(5-cyano-2-benzoxazolyl)piperidine (1.33g) was obtained as a brown-dark solid.

[1757] (3) Using the above-mentioned compound (409 mg) and the titlecompound (450 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-cyano-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(230 mg) was obtained as a white solid.

[1758] (4) The above-mentioned compound (226 mg) was dissolved in ethylacetate (1 mL), and 4 mol/L hydrochloric acid-ethyl acetate (1.1 mL) wasadded thereto. The mixture was stirred at room temperature for 18 hr.The reaction mixture was concentrated under reduced pressure, andsaturated aqueous sodium hydrogencarbonate solution was added to theresidue. The mixture was extracted with chloroform. The extract wasdried, and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography and crystallized from ethyl acetate to givethe title compound (869 mg) as a white powder.

[1759]¹H-NMR(DMSO-d₆)δ1.53-1.65(1H,m), 1.73-1.90(2H,m), 2.04-2.24(4H,m),2.27-2.37(1H,m), 2.68-3.12(8H,m), 3.60-3.98(3H,m), 4.40-4.69(2H,m),7.84(1H,dd,J=8.4,1.4 Hz), 7.92(1H,d,J=8.4 Hz), 8.32(1H,d,J=1.4 Hz).

Example 315

[1760] Synthesis of3-{(2S,4S)-4-[4-(5-methoxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1761] (1) Using the product (5.11 g) of Example 301 (1) and3-amino-4-methoxyphenol 2.72 g, and in the same manner as in Example 301(2), 1-benzyloxycarbonyl-4-(5-methoxy-2-benzoxazolyl)piperidine (4.35 g)was obtained as an orange oil.

[1762] (2) Using the above-mentioned compound (4.25 g), and in the samemanner as in Example 301 (3), 4-(5-methoxy-2-benzoxazolyl)piperidine(2.47 g) was obtained as a red-brown solid.

[1763] (3) Using the above-mentioned compound (0.767 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-methoxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.38 g) was obtained as a white solid.

[1764] (4) The above-mentioned compound (1.37 g) was dissolved inethanol (4 mL), and 4.1 mol/L hydrochloric acid-ethanol (6.5 mL) wasadded thereto. The mixture was stirred at room temperature for 16 hr.The reaction mixture was concentrated under reduced pressure and theresidue was crystallized from ethanol (10 mL) to give the title compound(0.953 g) as a white powder.

[1765]¹H-NMR(DMSO-d₆)δ2.12-2.43(5H,m), 2.90-4.07(16H,m),4.45-4.77(3H,m), 6.97(1H,dd,J=8.9,2.5 Hz), 7.28(1H,d,J=2.5 Hz),7.60(1H,d,J=8.9 Hz), 9.14(1H,brs), 10.67(1H,brs), 12.03(1H,brs).

Example 316

[1766] Synthesis of3-{(2S,4S)-4-[4-(2-benzothiazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1767] (1) Using the product (5.74 g) of Example 301 (1) and2-aminothiophenol (2.3 mL), and in the same manner as in Example 301(2), 4-(2-benzothiazolyl)-1-benzyloxycarbonylpiperidine (3.76 g) wasobtained as a yellow solid.

[1768] (2) The above-mentioned compound (986 mg) and thioanisole (1.0mL) were dissolved in trifluoroacetic acid (10 mL), and the mixture wasstirred at room temperature for 11 hr. The reaction mixture wasconcentrated under reduced pressure, and saturated aqueous sodiumhydrogencarbonate solution was added to the residue. The mixture wasextracted with chloroform. The extract was dried and concentrated underreduced pressure to give 4-(2-benzothiazolyl)piperidine (0.299 g) as awhite solid.

[1769] (3) Using the above-mentioned compound (297 mg) and the titlecompound (409 mg) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-4-[4-(2-benzothiazolyl)piperidino]-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(625 mg) was obtained as a white solid.

[1770]¹H-NMR(CDCl₃)δ1.41(4.5H,s), 1.46(4.5H,s), 1.82-2.06(3H,m),2.14-2.32(4H,m), 2.39-2.52(1H,m), 2.78-3.21(6H,m), 3.32(1H,t,J=10.0 Hz),3.63-4.12(3H,m), 4.37-4.79(3H,m), 7.35(1H,t,J=7.8 Hz), 7.46(1H,t,J=7.8Hz), 7.86(1H,d,J=7.8 Hz), 7.97(1H,d,J=7.8 Hz).

[1771] (4) The above-mentioned compound (621 mg) was dissolved in 1.1mol/L hydrochloric acid-methanol (6 mL), and the mixture was stirred atroom temperature for 2 days. The reaction mixture was concentrated underreduced pressure and the residue was crystallized from ethanol (6 mL) togive the title compound (423 mg) as a white powder.

[1772]¹H-NMR(DMSO-d₆)δ2.16-2.46(5H,m), 2.94-3.36(5H,m), 3.40-4.08(8H,m),4.47-4.78(3H,m), 7.44(1H,t,J=7.8 Hz), 7.52(1H,t,J=7.8 Hz),7.99(1H,d,J=7.8 Hz), 8.11(1H,d,J=7.8 Hz), 9.13(1H,brs), 10.82(1H,brs),12.14(1H,brs).

Example 317

[1773] Synthesis of3-{(2S,4S)-4-[4-(5-trifluoromethyl-2-benzothiazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine

[1774] (1) The product (2.96 g) of Example 301 (1),2-amino-4-trifluoromethylthiophenol hydrochloride (2.99 g) andtriethylamine (1.8 mL) were dissolved in ethanol (60 mL), and themixture was refluxed for 4 hr. The reaction mixture was concentratedunder reduced pressure, and 0.5 mol/L aqueous sodium hydroxide solutionwas added to the residue. The mixture was extracted with chloroform. Theextract was washed successively with 0.5 mol/L hydrochloric acid,saturated aqueous sodium hydrogencarbonate solution and brine, anddried. The solvent was evaporated under reduced pressure and the residuewas purified by silica gel chromatography to give1-benzyloxycarbonyl-4-(5-trifluoromethyl-2-benzothiazolyl)piperidine(1.75 g) as a pale-yellow oil.

[1775] (2) The above-mentioned compound (1.74 g) was dissolved in 30%hydrogen bromide-acetic acid solution (8 mL), and the mixture wasstirred at room temperature for 1 hr. Diethyl ether (10 mL) was added tothe reaction mixture, and the precipitated solid was collected byfiltration. The saturated aqueous sodium hydrogencarbonate solution wasadded to the precipitated solid, and the mixture was extracted withchloroform. The extract was dried and concentrated under reducedpressure to give 4-(5-trifluoromethyl-2-benzothiazolyl)piperidine (0.943g) as a pale-yellow solid.

[1776] (3) Using the above-mentioned compound (0.923 g) and the titlecompound (0.901 g) of Reference Example 12, and in the same manner as inExample 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-trifluoromethyl-2-benzothiazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.60 g) was obtained as a white solid.

[1777] (4) The above-mentioned compound (1.60 g) was dissolved in 4.1mol/L hydrochloric acid-ethanol (7 mL), and the mixture was stirred atroom temperature for 2 days. The reaction mixture was concentrated underreduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added to the residue. The mixture was extracted withchloroform. The extract was dried and concentrated under reducedpressure. The residue was purified by silica gel chromatography andcrystallized from diethyl ether to give the title compound (0.848 g) asa white powder.

[1778]¹H-NMR(DMSO-d₆)δ1.52-1.65(1H,m), 1.72-1.88(2H,m), 2.04-2.20(4H,m),2.22-2.33(1H,m), 2.67-3.23(8H,m), 3.58-3.92(3H,m), 4.40-4.70(2H,m),7.74(1H,dd,J=8.4,1.5 Hz), 8.31(1H,d,J=1.5 Hz), 8.34(1H,d,J=8.4 Hz).

Example 318

[1779] Synthesis of3-{(2S,4S)-4-[4-(6-fluoro-3-benz[d]isoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidinedihydrochloride

[1780] (1) Using 4-(6-fluoro-3-benz[d]isoxazolyl)piperidine (0.54 g) andthe title compound (0.614 g) of Reference Example 12, and in the samemanner as in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-fluoro-3-benz[d]isoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.01 g) was obtained as a white powder.

[1781] (2) Using the above-mentioned compound (1.00 g), and in the samemanner as in Example 133 (2), the title compound (0.38 g) was obtainedas a white powder.

[1782]¹H-NMR(500 MHz,DMSO-d₆)δ2.05-2.46(5H,m), 2.92-4.20(13H,m),4.49-4.73(3H,m), 7.32-7.36(1H,m), 7.72-7.74(1H,m), 8.20(1H,brs),9.10(1H,brs), 10.60(1H,brs), 12.22(1H,brs).

Example 319

[1783] Synthesis of3-{(2S,4S)-4-(2-[(5-cyano-2-pyridyl)amino]ethyl}amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidinetrihydrochloride

[1784] (1) Using N-(5-cyano-2-pyridyl)ethylenediamine (0.656 g) and thetitle compound (1.20 g) of Reference Example 12, and in the same manneras in Example 70 (1),3-{(2S,4S)-1-tert-butoxycarbonyl-4-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine(1.46 g) was obtained as a white solid.

[1785] (2) The above-mentioned compound (656 mg) was dissolved in ethylacetate (4 mL), and 4 mol/L hydrochloric acid-ethyl acetate (4 mL) wasadded thereto. The mixture was stirred at room temperature for 12 hr.The precipitated solid was collected by filtration to give the titlecompound (666 mg) as a white powder.

[1786]¹H-NMR(DMSO-d₆)δ2.03-2.19(1H,m), 2.87-2.98(1H,m), 3.06(1H,t,J=6.5Hz), 3.10-3.25(3H,m), 3.45-4.10(7H,m), 4.47-4.74(3H,m), 6.67(1H,d,J=8.9Hz), 7.76(1H,dd,J=8.9,2.2 Hz), 8.03(1H,brs), 8.46(1H,d,J=2.2 Hz),8.96(1H,brs), 9.96(2H,brs), 10.64(1H,brs).

Example 320

[1787] Synthesis of3-[(2S,4S)-4-(N-acetyl-N-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino)-2-pyrrolidinylcarbonyl]-1,3-thiazolidinedihydrochloride

[1788] (1)3-{(2S,4S)-1-tert-Butoxycarbonyl-4-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino-2-pyrrolidinylcarbonyl}-1,3-thiazolidine[product of Example 319 (1), 800 mg] and triethylamine (0.42 mL) weredissolved in dichloromethane (20 mL), and acetyl chloride (0.18 mL) wasadded thereto under ice-cooling. The mixture was stirred at roomtemperature for 5 hr. The reaction mixture was added to saturatedaqueous sodium hydrogencarbonate solution and the mixture was extractedwith chloroform. The extract was washed with brine, dried, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give3-[(2S,4S)-4-(N-acetyl-N-{2-[(5-cyano-2-pyridyl)amino]ethyl}amino)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine(786 mg) as a white solid.

[1789] (2) The above-mentioned compound (380 mg) was dissolved in ethylacetate (3 mL), and 4 mol/L hydrochloric acid-ethyl acetate (1 mL) wasadded thereto. The mixture was stirred at room temperature for 3 hr. Theprecipitated solid was collected by filtration to give the titlecompound (314 mg) as a white powder.

[1790]¹H-NMR(DMSO-d₆)δ1.95-2.10(4H,m), 2.62-2.80(1H,m),3.00-3.90(11H,m), 4.28-4.77(4H,m), 6.64(1H,d,J=8.8 Hz),7.73(1H,dd,J=8.8,2.2 Hz), 7.95(1H,brs), 8.35(1H,brs), 8.42(1H,d,J=2.2Hz), 9.96(1H,brs).

[1791] The structures of the compound obtained in the above-mentionedExamples are all shown in Tables 1-40. TABLE 1

Example No. X Y Z salt  1

CH₂ CN CF₃CO₂H  2

CH₂ CN HCl  3

CH₂ CN 2HCl  4

CH₂ CN CF₃CO₂H  5

CH₂ CN HCl  6

CH₂ CN HCl  7

CH₂ CN HCl  8

CH₂ CN HCl  9

CH₂ CN HCl 10

CH₂ CN HCl 11

CH₂ CN HCl

[1792] TABLE 2

Example No. X Y Z salt 12

CH₂ CN HCl 13

CH₂ CN HCl 14

CH₂ CN CF₃CO₂H 15

CH₂ CN CF₃CO₂H 16

CH₂ CN HCl 17

CH₂ CN CF₃CO₂H 18

CH₂ CN 2HCl 19

CH₂ CN 2HCl 20

CH₂ CN 2CF₃CO₂H 21

CH₂ CN 2HCl

[1793] TABLE 3

Ex- am- ple No. X Y Z salt 22

CH₂ CN CF₃CO₂H 23

CH₂ CN HCl 24

CH₂ CN HCl 25

CH₂ CN HCl 26

CH₂ CN HCl 27

CH₂ CN HCl 28

CH₂ CN 2HCl 29

CH₂ CN 2HCl 30

CH₂ CN 2HCl 31

CH₂ CN 2HCl 32

CH₂ CN 2HCl

[1794] TABLE 4

Example No. X Y Z salt 33

CH₂ CN 2HCl 34

CH₂ CN 3CF₃CO₂H 35

CH₂ CN 2CF₃CO₂H 36

CH₂ CN 2HCl 37

CH₂ CN 2HCl 38

CH₂ CN 2HCl 39

CH₂ CN 2HCl 40

CH₂ CN HCl 41

CH₂ CN HCl 42

CH₂ CN HCl 43

CH₂ CN HCl

[1795] TABLE 5

Example No. X Y Z salt 44

CH₂ CN HCl 45

CH₂ CN 2CF₃CO₂H 46

CH₂ CN 2CF₃CO₂H 47

CH₂ CN 2HCl 48

CH₂ CN CF₃CO₂H 49

CH₂ CN 2HCl 50

CH₂ CN 2HCl 51

CH₂ CN 2HCl 52

CH₂ CN 2HCl 53

S H 2HCl

[1796] TABLE 6

Example No. X Y Z salt 54

S H HCl 55

S H HCl 56

S H HCl 57

S H HCl 58

S H 2HCl 59

S H HCl 60

S H HCl 61

S H HCl 62

S H 2HCl 63

S H 2HCl 64

S H 2HCl

[1797] TABLE 7

Example No. X Y Z salt 65

S H 3HCl 66

S H — 67

S H — 68

S H 2HCl 69

S H HCl 70

S H 2HCl 71

S H 2HCl 72

S H HCl 73

S H 2HCl

[1798] TABLE 8

Example No. X Y Z salt 74

S H 2HCl 75

S H 2HCl 76

S H HCl 77

S H HCl 78

S H 2HCl 79

S H 2HCl 80

S H 2HCl 81

S H 3HCl 82

S H HCl 83

S H HCl 84

S H 2HCl

[1799] TABLE 9

Example No. X Y Z salt 85

CH₂ H 2HCl 86

S H HCl 87

S H 2HCl 88

S H 2HCl 89

S H 2HCl 90

S H 2HCl 91

S H 2HCl 92

S H 2HCl 93

S H HCl 94

S H HCl

[1800] TABLE 10

Example No. X Y Z salt  95

S H HCl  96

S H 2CF₃CO₂H  97

S H 2HCl  98

S H HCl  99

S H 2HCl 100

S H 2HCl 101

S H 2HCl 102

S H 2HCl 103

S H CF₃CO₂H 104

S H 2HCl 105

S H 2HCl

[1801] TABLE 11

Example No. X Y Z salt 106

S H 2HCl 107

S H 2CF₃CO₂H 108

S H 2CF₃CO₂H 109

S H 2HCl 110

S H — 111

S H HCl 112

S H HCl 113

S H HCl 114

S H HCl 115

S H HCl

[1802] TABLE 12

Example No. X Y Z salt 116

S H HCl 117

S H HCl 118

S H CF₃CO₂H 119

S H CF₃CO₂H 120

S H CF₃CO₂H 121

S H — 122

S H HCl 123

S H HCl 124

S H HCl 125

S H 2HCl

[1803] TABLE 13

Example No. X Y Z salt 126

S H 2HCl 127

S H 2HCl 128

S H 3HCl 129

S H 2CF₃CO₂H 130

S H 2HCl 131

S H 2HCl 132

S H 2HCl 133

S H 2HCl 134

S H 2HCl

[1804] TABLE 14

Example No. X Y Z salt 135

S H 2HCl 136

S H 2HCl 137

S H 2HCl 138

S H 2HCl 139

S H 2HCl 140

S H 2HCl 141

S H 2HCl 142

S H 2HCl

[1805] TABLE 15

Example No. X Y Z salt 143

S H 2HCl 144

S H 3HCl 145

S H 2HCl 146

S H 3HCl 147

S H 2HCl 148

S H 3HCl 149

S H 3HCl 150

S H 3HCl 151

S H 3HCl

[1806] TABLE 16

Example No. X Y Z salt 152

S H 3HCl 153

S H 3HCl 154

S H 2CF₃CO₂H 155

S H 2HCl 156

S H 3HCl 157

S H 2HCl 158

S H 2HCl 159

S H 3HCl

[1807] TABLE 17

Example No. X Y Z salt 160

S H 3HCl 161

CH₂ H 3HCl 162

S H 3HCl 163

S H 3HCl 164

S H 3HCl 165

S H 3HCl 166

S H 3HCl 167

S H 3HCl

[1808] TABLE 18

Example No. X Y Z salt 168

S H 2HCl 169

S H 3HCl 170

S H 3HCl 171

S H 2HCl 172

S H 3HCl 173

S H 3HCl 174

S H 3HCl 175

S H 3HCl

[1809] TABLE 19

Example No. X Y Z salt 176

S H 3HCl 177

S H 3HCl 178

S H 2HCl 179

S H 3HCl 180

S H 3HCl 181

S H 3HCl 182

CH₂ H 3HCl

[1810] TABLE 20

Example No. X Y Z salt 183

S H 3HCl 184

S H 2HCl 185

S H 2HCl 186

CH₂ H 3HCl 187

S H 3HCl 188

S H 3HCl 189

S H 3HCl 190

S H 3HCl

[1811] TABLE 21

Example No. X Y Z salt 191

S H 2HC 192

S H 3HCl 193

S H 3HCl 194

S H 2HC 195

S H 2HC 196

S H 2HCl 197

S H 3HCl

[1812] TABLE 22

Example No. X Y Z salt 198

S H 3HCl 199

S H 2HCl 200

S H 2HCl 201

S H 2HCl 202

S H 2HCl 203

S H 2HCl 204

S H 2HCl 205

S H 3HCl

[1813] TABLE 23

Example No. X Y Z salt 206

S H 4HCl 207

S H 2HCl 208

S H 3HCl 209

S H 3HCl 210

S H 3HCl 211

S H 3HCl 212

S H 3HCl

[1814] TABLE 24

Example No. X Y Z salt 213

S H 3HCl 214

S H 3HCl 215

S H 3HCl 216

S H 3HCl 217

S H 3HCl 218

S H 3HCl 219

S H 3HCl

[1815] TABLE 25

Example No. X Y Z salt 220

S H 3HCl 221

S H 3HCl 222

S H 3HCl 223

S H 3HCl 224

S H 3HCl 225

S H 3HCl 226

S H 3HCl

[1816] TABLE 26

Example No. X Y Z salt 227

S H 3HCl 228

S H 3HCl 229

S H 3HCl 230

S H 2HCl 231

S H 3HCl 232

S H 3HBr 233

S H 3HBr

[1817] TABLE 27

Example No. X Y Z salt 234

S H 3HBr 235

S H 3HCl 236

S H 3HCl 237

S H 3HCl 238

S H 3HCl 239

S H 2HCl

[1818] TABLE 28

Example No. X Y Z salt 240

S H 2HCl 241

S H 2HCl 242

S H 2HCl 243

S H 3HCl 244

S H 3HCl 245

S H 2HCl

[1819] TABLE 29

Example No. X Y Z salt 246

S H 2HCl 247

S H 2HCl 248

S H 3HCl 249

S H 3HCl 250

S H 3HCl 251

S H 3HCl

[1820] TABLE 30

Example No. X Y Z salt 252

S H 3HCl 253

S H 3HCl 254

S H 3HCl 255

S H 1.5(CO₂H)₂ 256

S H 3HCl 257

S H 3HCl 258

S H 3HCl

[1821] TABLE 31

Example No. X Y Z salt 259

S H 3HCl 260

S H 2HCl 261

S H 2HCl 262

S H 3HCl 263

S H 3HCl 264

S H 3HCl

[1822] TABLE 32

Example No. X Y Z salt 265

S H 3HCl 266

S H 3HCl 267

S H 3HCl 268

S H 3HCl 269

S H 2HCl 270

S H 2HCl

[1823] TABLE 33

Example No. X Y Z salt 271

S H 2HCl 272

S H 3HCl 273

S H 2HCl 274

S H 2HCl 275

S H 2HCl 276

S H 2HCl

[1824] TABLE 34

Example No. X Y Z salt 277

S H 2HCl 278

S H 3HCl 279

S H 3HCl 280

S H 3HCl 281

S H 3HCl 282

S H —

[1825] TABLE 35

Example No. X Y Z salt 283

S H 3HCl 284

S H 2HCl 285

S H 2HCl 286

S H 2HCl 287

S H 2HCl 288

S H 2HCl 289

S H 2HCl

[1826] TABLE 36

Exam- ple No. X Y Z salt 290

S H 2HCl 291

S H 3HCl 292

S H 3HCl 293

S H 2HCl 294

S H 2HCl 295

S H 2HCl

[1827] TABLE 37

Example No. X Y Z salt 296

S H 3HCl 297

S H 3HCl 298

S H 2HCl 299

S H 2HCl 300

S H 2HCl 301

S H 3HCl

[1828] TABLE 38

Example No. X Y Z salt 302

S H 3HCl 303

S H 3HCl 304

S H 3HCl 305

S H 3HCl 306

S H — 307

S H —

[1829] TABLE 39

Exam- ple No. X Y Z salt 308

S H — 309

S H — 310

S H 2HCl 311

S H — 312

S H — 313

S H 2HCl

[1830] TABLE 40

Example No. X Y Z salt 314

S H — 315

S H 2HCl 316

S H 2HCl 317

S H — 318

S H 2HCl 319

S H 3HCl 320

S H 2HCl

[1831] The compound of the present invention showed a potent DPP-IVinhibitory activity in Experimental Example 1 shown below.

Experimental Example 1 (Plasma DPP-IV Inhibitory Activity)

[1832] The plasma DPP-IV inhibitory activity of human and rat wasmeasured by the fluorescence assay method. Using Gly-Pro-MCA (PeptideInstitute Inc.) as a DPP-IV specific fluorescent substrate, reactionsolutions having the following compositions and containing testsubstances having various concentrations were incubated at roomtemperature for 60 min and the measured (SPECTRA FLUOR, TECAN)fluorescent intensity (Exitation 360 nm/Emission 465 nm) was taken asthe DPP-IV activity. Rat or human plasma (10-fold diluted solution)  20μL/well fluorescent substrate (100 μmol/L)  20 μL/well test substance 20 μL/well buffer (0.003% Brij-35 containing PBS) 140 μL/well totalamount 200 μL/well

[1833] The inhibitory rate relative to the solvent addition group wascalculated and IC₅₀ values were determined by logistic analysis.

[1834] The IC₅₀ values of the plasma DPP-IV inhibitory activity of thepresent invention as determined by the method above are shown in thefollowing table. Example Human plasma DPP-IV Rat plasma DPP-IV compoundInhibitory activity Inhibitory activity No. IC₅₀ (nM) IC₅₀ (nM) 5 0.180.17 12 0.13 0.15 20 0.54 0.41 24 0.51 0.64 29 0.30 0.22 39 1.1 0.55 884.8 6.1 99 6.8 9.4 143 1.5 2.1 186 3.7 4.2 189 0.95 1.0 212 0.45 0.75242 0.33 0.34 279 0.73 0.79 296 1.1 1.9 303 0.61 1.1

[1835] As shown in the following, the plasma DPP-IV inhibitory activityof the compound of Japanese Patent Application under PCT laid-open underkohyo No. 9-509921 and the compound of WO99/61431 is not sufficient.Human plasma DPP-IV Inhibitory activity Known compound IC₅₀ (nM)(S)-2-cyano-1-L-prolylpyrrolidine 2.9 hydrochloride3-L-prolyl-1,3-thiazolidine 538

Industrial Applicability

[1836] From the foregoing Experimental Example and variouspharmacological experiments, the compounds of the present inventionexhibit a potent DPP-IV inhibitory activity and are useful for theprophylaxis or treatment of diabetes or the prophylaxis or treatment ofobesity or the prophylaxis or treatment of HIV infection, cancermetastasis, dermopathy, prostatic hyperplasia, periodontitis orautoimmune disease, and the like.

[1837] This application is based on patent application Nos. 243217/2000and 400296/2000 filed in Japan, the contents of which are herebyincorporated by reference.

What is claimed is:
 1. An L-proline derivative of the formula (I)

wherein X shows —NR¹R² wherein R¹ and R² may be the same or differentand each is independently a hydrogen atom, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or maybe bonded to each other to form a heterocycle optionally containing 1 or2 nitrogen atoms or oxygen atoms, the heterocycle optionally beingcondensed with an aromatic ring optionally having substituents, and thespirocycle optionally being a spiro ring, —NR³COR⁴ wherein R³ and R⁴ arethe same or different and each is independently a hydrogen atom, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl orheteroarylalkyl, —NR⁵CONR⁶R⁷ or —NR⁵CH₂CH₂NR⁶R⁷ wherein R⁵, R⁶ and R⁷are the same or different and each is independently hydrogen atom,alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or R⁶ and R⁷ may be bonded to each other to form aheterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms,the heterocycle optionally being condensed with an aromatic ringoptionally having substituents, —NR⁸SO₂R⁹ wherein R⁸ and R⁹ are the sameor different and each is independently a hydrogen atom, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or —OR¹⁰ or —OCOR¹¹ wherein R¹⁰ and R¹¹ are each ahydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl, Y is CH₂, CH—OH, S, S═O or SO₂, Z is ahydrogen atom or a cyano, and of the above-mentioned groups, alkyl,aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl,cycloalkylalkyl and heterocycle each optionally have substituents, or apharmaceutically acceptable salt thereof.
 2. The L-proline derivative ofclaim 1, wherein X of the formula (I) is a substituent selected from theformulas

wherein

is a single bond or a double bond, R¹² is alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —NR¹⁴R¹⁵,—OR¹⁶, —COR¹⁷, —CO₂R¹⁸, —CONR¹⁹R²⁰ or —SO₂R²¹ wherein R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are the same or different and each isindependently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, or R¹⁴ and R⁵, andR¹⁹ and R²⁰ may be bonded to each other to form heterocycles eachoptionally containing 1 or 2 nitrogen atoms or oxygen atoms, saidheterocycle optionally being condensed with an aromatic ring optionallyhaving substituents, R¹³ is a hydrogen atom, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, m is 1or 2, and A is a carbon atom or a nitrogen atom, provided that i) when Ais a carbon atom, A may be substituted by a hydroxyl group, carboxyl oralkoxycarbonyl, and ii) when A is a nitrogen atom,

is a single bond, of the above-mentioned groups, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl andheterocycle each optionally have substituents, or a pharmaceuticallyacceptable salt thereof.
 3. The L-proline derivative of claim 1 or 2,wherein X of the formula (I) is a substituent selected from the formulas

wherein R²² is a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl or heteroarylalkyl, R²³ and R²⁴ are the sameor different and each is independently a hydrogen atom, alkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, halogen, haloalkyl, cyano,nitro, —NR²⁵R²⁶, —NHSO₂R²⁷, —OR²⁸, —COOR²⁹, —CONHSO₂R³⁰—SO₂OR³¹, —SO₂R³²or —CONR³³R³⁴ wherein R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³ andR³⁴ are the same or different and each is independently a hydrogen atom,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl or haloalkyl, or R²⁵ and R²⁶, and R³³ and R³⁴ may bebonded to each other to form heterocycles each optionally containing 1or 2 nitrogen atoms or oxygen atoms, said heterocycle optionally beingcondensed with an aromatic ring optionally having substituents, a, b, c,d, e, f and g are all carbon atoms, or any one or two thereof is(are)nitrogen atom(s) and the rest is a carbon atom, n is 0, 1, 2 or 3, and Ais a carbon atom or a nitrogen atom, provided that when A is a carbonatom, A may be substituted by a hydroxyl group, carboxyl oralkoxycarbonyl, and of the above-mentioned groups, alkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl andheterocycle each optionally have substituents, or a pharmaceuticallyacceptable salt thereof.
 4. The L-proline derivative of any of claims 1to 3, wherein, in the formula (I), the asymmetric carbon, to which X isbonded, is expressed by an S configuration, X is a group of the formula(VI) or (VII), R²³ and R²⁴ are the same or different and each is nitro,cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, halogen or haloalkyl, Y is a sulfur atomand Z is a hydrogen atom, or a pharmaceutically acceptable salt thereof.5. The L-proline derivative of claim 1, wherein, in the formula (I), Xis a hydroxyl group, phenylamino optionally having substituents,2-pyridylamino optionally having substituents, 3-pyridazinylaminooptionally having substituents or 2-pyrimidinylamino optionally havingsubstituents, and the asymmetric carbon, to which X is bonded, isexpressed by an S configuration, or a pharmaceutically acceptable saltthereof.
 6. A compound of the formula (I-a)

wherein X shows —NR¹R² wherein R¹ and R² may be the same or differentand each is independently a hydrogen atom, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or maybe bonded to each other to form a heterocycle optionally containing 1 or2 nitrogen atoms or oxygen atoms, the heterocycle optionally beingcondensed with an aromatic ring optionally having substituents, and theheterocycle optionally being a spiro ring, —NR³COR⁴ wherein R³ and R⁴are the same or different and each is independently a hydrogen atom,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl,heteroaryl or heteroarylalkyl, —NR⁵CONR⁶R⁷ or —NR⁵CH₂CH₂NR⁶ R⁷ whereinR⁵, R⁶ and R⁷ are the same or different and each is independently ahydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl, or R⁶ and R⁷ may be bonded toeach other to form a heterocycle optionally containing 1 or 2 nitrogenatoms or oxygen atoms, said heterocycle optionally being condensed withan aromatic ring optionally having substituents, or —NR⁸SO₂R⁹ wherein R⁸and R⁹ are the same or different and each is independently a hydrogenatom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, Y is CH₂, CH—OH, S, S═O or SO₂, Z is a hydrogen atom ora cyano, R³⁵ is —COR⁴¹ wherein R⁴¹ is a hydrogen atom, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, or —COOR⁴² wherein R⁴² is alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, and ofthe above-mentioned groups, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl and heterocycle eachoptionally have substituents.
 7. A compound of the formula (I-b)

wherein Z is a hydrogen atom or a cyano, and R³⁵ is —COR⁴¹ wherein R⁴¹is a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl, or —COOR⁴² wherein R⁴² is alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl, and of the above-mentioned groups, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl eachoptionally have substituents. The present invention further relates tothe following compositions for pharmaceutical agents.
 8. Apharmaceutical composition containing an L-proline derivative of any ofclaims 1 to 5 or a pharmaceutically acceptable salt thereof, and apharmacologically acceptable carrier.
 9. A DPP-IV inhibitor containingan L-proline derivative of any of claims 1 to 5 or a pharmaceuticallyacceptable salt thereof as an active ingredient.
 10. A therapeutic agentfor the disease where DPP-IV is involved, which contains an L-prolinederivative of any of claims 1 to 5 or a pharmaceutically acceptable saltthereof as an active ingredient.
 11. The therapeutic agent of claim 10,wherein the aforementioned disease is diabetes, obesity, HIV infection,cancer metastasis, dermopathy, prostatic hyperplasia, periodontitis orautoimmune disease.